JP2007522213A - Method for producing substituted triazole compounds - Google Patents

Abstract

本発明は、選択的キナーゼ又はデュアル−キナーゼ媒介障害の処置又は改善において有用な式：（Ｉ）の置換されたトリアゾール化合物の新規な製造方法を目的とし；式中、Ｒ１及びＲ２は請求項中で定義される通りである。本発明の方法は、置換されたトリアゾール化合物の所望の位置異性体を優先的に製造する。[Chemical 1]

The present invention is directed to a novel process for the preparation of substituted triazole compounds of formula (I) useful in the treatment or amelioration of selective kinase or dual-kinase mediated disorders; wherein R1 and R2 are in the claims As defined in. The process of the present invention preferentially produces the desired regioisomer of substituted triazole compounds.

Description

Cross-reference to related applications

  This application is hereby incorporated by reference into US Provisional Application Nos. 60 / 543,721 and 29 October 2004, both of which are incorporated herein by reference in their entirety. Claim the benefit of US Provisional Application No. 60 / 623,681, filed in.

The present invention is directed to novel methods for the production of substituted triazole compounds useful in the treatment or amelioration of selective kinase or dual-kinase mediated disorders. The process of the present invention preferentially produces regioisomers of compounds of formula (I).

BACKGROUND OF THE INVENTION The present invention is directed to a process for the preparation of compounds of formula (I). The compounds of formula (I) are selective kinase or dual-kinase inhibitors useful in methods for treating or ameliorating a kinase or dual-kinase mediated disorder. In particular, the kinase is selected from cyclin dependent kinases and tyrosine kinases. More specifically, the kinase is cyclin dependent kinase-1, cyclin-dependent kinase-2, cyclin-dependent kinase-4, vascular endothelial growth factor receptor-2, endothelial growth factor receptor or human epidermal growth factor receptor. Selected from Body-2.

  Lin et al. Discloses a number of methods for the preparation of substituted triazole compounds in US Pat. No. 6,057,028, the contents of which are incorporated herein by reference. Lin et al. Requires the use of hydrazine (which is toxic, mutagenic and possibly explosive) and / or requires chromatographic separation of products and / or intermediates and / or Of regioisomers (which must be separated by any means), making these methods unsuitable for large scale production.

  A known process for the preparation of substituted triazoles comprising reacting an unsubstituted triazole with a suitably selected reagent results in the formation of regioisomers of substituted triazole compounds. This occurs because a reagent that reacts with an unsubstituted triazole reacts with more than one nitrogen atom of the triazole, thereby yielding compounds with various substitution patterns--regioisomers.

Thus, there remains a need for a process for producing substituted triazole compounds that preferentially produces the regioisomer of formula (I) as defined herein below.
WO02 / 057240 pamphlet

SUMMARY OF THE INVENTION The present invention provides compounds of formula (I):

[Where:
R ₁ is selected from the group consisting of C _1-8 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
Where cycloalkyl, heterocyclyl, aryl and heteroaryl are:
(A) C _1-8 alkyl (optionally on the terminal carbon —C (O) H, —C (O) (C _1-8 ) alkyl, —CO ₂ (C _1-8 ) alkyl, amino, C ₁ Substituted with a substituent selected from the group consisting of _-8 alkylamino, di (C _1-8 alkyl) amino, cyano, (halo) _1-3 , hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl. be able to),
(B) C _1-8 alkoxy (optionally substituted on the terminal carbon with a substituent selected from the group consisting of (halo) _1-3 and hydroxy),
(C) -C (O) H, -C (O) ( _C1-8 ) alkyl;
_{(D) -CO 2 (C 1-8} ) alkyl;
(E) amino (substituted with two substituents independently selected from the group consisting of hydrogen, C _1-8 alkyl and —SO ₂ — (C _1-8 ) alkyl),
(F) -C (O) amino, wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and _C1-8 alkyl;
(G) —SO ₂ — {heterocyclyl and amino (wherein amino is hydrogen, C _1-8 alkyl, —C _1-8 alkylamino (wherein amino is independently from the group consisting of hydrogen and C _1-8 alkyl) Substituted with 2 substituents selected) and substituted with 2 substituents independently selected from the group consisting of heteroaryl) and substituted with 1 substituent selected from the group consisting of ing},
(H) cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally 1-3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro Can be substituted with;
And where heterocyclyl can be optionally substituted with 1 to 2 oxo substituents; and where cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally C _1-8 alkyl (wherein alkyl is _Is substituted on the terminal carbon with a substituent selected from the group consisting of amino, C _1-8 alkylamino, di (C _1-8 alkyl) amino, cyano, (halo) _1-3 , hydroxy and nitro. And can be substituted with a substituent selected from the group consisting of C _1-8 alkoxy, amino, C _1-8 alkylamino and di (C _1-8 alkyl) amino)
Substituted with a substituent selected from the group consisting of:
R ₃ is: C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl {where C _1-8 alkyl, C _2-8 alkenyl and C _2-8 alkynyl are optionally —C on the terminal carbon (O) H, -C (O ) (C 1-8) _alkyl, -CO _{2 (C 1-8)} alkyl, _{amino, C 1-8} alkylamino, di _{(C 1-8} alkyl) amino, cyano, (Halo) _2-3 , hydroxy, nitro, aryl and heteroaryl, where aryl and heteroaryl are optionally C _1-8 alkyl, cyano, (halo) _1-3 (C _1-8 ) alkyl, (halo) _1-3 Substituted with 1 to 5 substituents independently selected from the group consisting of (C _1-8 ) alkoxy, hydroxy, hydroxy (C _1-8 ) alkyl, hydroxy (C _1-8 ) alkoxy and nitro Can be substituted with a substituent selected from the group consisting of:
Cycloalkyl, heterocyclyl, aryl, heteroaryl {where cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, hydroxy and nitro It is possible;
Where aryl and heteroaryl may be optionally substituted with (halo) _1-3 ;
And where cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally:
(A) C _1-8 alkyl, C _2-8 alkenyl (wherein C _1-8 alkyl and C _2-8 alkenyl are optionally —C (O) H, —C (O) (C _{1 -8) alkyl,} -CO _{2 (C 1-8)} alkyl, _{amino, C 1-8} alkylamino, di _{(C 1-8} alkyl) amino, cyano, _{(halo) 2-3,} hydroxy, nitro, cycloalkyl , Substituted with a substituent selected from the group consisting of heterocyclyl, aryl and heteroaryl),
(B) -CH (OH)-( _C1-8 ) alkyl,
(C) C _1-8 alkoxy (optionally substituted on the terminal carbon with a substituent selected from the group consisting of (halo) _2-3 and hydroxy),
(D) -C (O) H, -C (O) ( _C1-8 ) alkyl;
_{(E) -CO 2 (C 1-8} ) alkyl;
(F) amino (substituted with two substituents independently selected from the group consisting of hydrogen, C _1-8 alkyl and —C (O) (C _1-8 ) alkyl),
(G) -C (O) amino, wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and _C1-8 alkyl;
(H) —SO ₂ — {heterocyclyl and amino (wherein amino is hydrogen, C _1-8 alkyl and —C _1-8 alkylamino (wherein amino is independently from the group consisting of hydrogen and C _1-8 alkyl); Substituted with two substituents independently selected from the group consisting of two substituents selected) and substituted with one substituent selected from the group consisting of} ,
_{(I) -NH-SO 2 -} (C 1-8) alkyl,
(J) substituted with 1 to 2 substituents independently selected from the group consisting of cycloalkyl, heterocyclyl (optionally substituted with 1 to 2 oxo substituents), aryl and heteroaryl Selected from the group consisting of amino;
Where amino is hydrogen, C _1-8 alkyl, cycloalkyl, aryl and heteroaryl (where cycloalkyl, aryl and heteroaryl are optionally C _1-8 alkyl, cyano, (halo) _1-3 (C _{1 -8} ) 1 independently selected from the group consisting of alkyl, (halo) _1-3 (C _1-8 ) alkoxy, hydroxy, hydroxy (C _1-8 ) alkyl, hydroxy (C _1-8 ) alkoxy and nitro Substituted with 2 substituents independently selected from the group consisting of ˜5 substituents);
Provided that when R ³ is aryl or heteroaryl, where aryl or heteroaryl can optionally be substituted with — (CH ₂ ) ₀ -2 —CO ₂ (C _1-8 ) alkyl group, The — (CH ₂ ) _0-2 —CO ₂ (C _1-8 ) alkyl group is not bonded in the ortho position to the bond identified by an asterisk in the compound of formula (I);
Further, provided that when R ³ is cycloalkyl or heterocyclyl, where cycloalkyl or heterocyclyl can be optionally substituted, the substituent on cycloalkyl or heterocyclyl is — (CH ₂ ) _0-2- CO Other than ₂ (C _1-8 ) alkyl]
And a method for producing a pharmaceutically acceptable salt thereof;

A suitably substituted compound of formula (II) is reacted with diphenylcyanocarboimidate in a first organic solvent to give the corresponding compound of formula (III);

Reacting a compound of formula (III) with a suitably substituted compound of formula (IV) in a second organic solvent to give the corresponding compound of formula (I).

  The present invention further provides a compound of formula (Ia)

Intended to produce a compound of

Reacting 4-aminobenzenesulfonamide with diphenylcyanocarboimidate in a first organic solvent to give N- [4- (aminosulfonyl) phenyl] -N'-cyanocarbamic acid phenyl ester;

N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester is reacted with 2,6-difluorobenzoic hydrazide in a second organic solvent to give the corresponding compound of formula (Ia) Comprising providing.

  The present invention is further directed to a novel crystalline form of the compound of formula (Ia) as well as a novel process for preparing the crystalline form of the compound of formula (Ia).

The present invention is further directed to novel crystalline salts of the compounds of formula (Ia). More specifically, the present invention is directed to CH ₃ SO ₃ H, HCl, HBr and H ₂ SO ₄ salts of compounds of formula (Ia). The present invention is further directed to a novel process for preparing salts of the compounds of formula (Ia). The present invention is further directed to a pharmaceutical composition comprising any of the salts described herein and a pharmaceutically acceptable carrier.

  The present invention is further directed to products produced according to any of the methods disclosed herein.

  An example of the present invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound produced according to any of the methods described herein. An example of the invention is a pharmaceutical composition prepared by mixing a compound produced according to any of the methods described herein and a pharmaceutically acceptable carrier. Exemplifying the invention is a method of preparing a pharmaceutical composition comprising mixing a compound produced according to any of the methods described herein and a pharmaceutically acceptable carrier. is there.

Detailed Description of the Invention The present invention provides compounds of formula (I)

[Wherein R ¹ and R ³ are as defined above]
It aims at the manufacturing method of this compound. The compounds of formula (I) are useful in the treatment or amelioration of selective kinase or dual-kinase mediated disorders.

  One aspect of the present invention is a process for preparing a compound of formula (Ia).

In one embodiment of the invention, R ¹ is selected from the group consisting of aryl and heteroaryl, wherein the aryl or heteroaryl group can be optionally substituted as defined above. Preferably, R ¹ is aryl, wherein the aryl group can be optionally substituted with aminosulfonyl. More preferably, R ¹ is 4-aminosulfonylphenyl.

In one embodiment of the invention, R ³ is selected from the group consisting of aryl and heteroaryl, wherein the aryl or heteroaryl group can be optionally substituted as defined above. Preferably R ³ is aryl, where aryl is substituted with 1 to 3 halos. More preferably, R ³ is 2,6-difluorophenyl.

In one embodiment of the invention, R ¹ is 4-aminosulfonylphenyl and R ³ is 2,6-difluorophenyl.

  In one embodiment of the present invention, the method of the present invention provides the regioisomer of formula (I) in a ratio greater than or equal to 10: 1, preferably greater than or equal to 25: 1. Is produced in a ratio greater than or equal to 50: 1.

  In one embodiment of the present invention, the method of the present invention provides the regioisomer of formula (Ia) in a ratio greater than or equal to 10: 1, preferably greater than or equal to 25: 1. Is produced in a ratio greater than or equal to 50: 1.

  Unless otherwise stated, the term “alkyl” refers to from 1 to 8 hydrogen-substituted carbon atoms; preferably from 1 to 6 hydrogen-substituted carbon atoms; and most preferably from 1 to 4 hydrogen-substituted carbon atoms only. Saturated straight chain or branched chain. The term “alkenyl” refers to a partially unsaturated linear or branched alkyl chain containing at least one double bond. The term “alkynyl” refers to a partially unsaturated linear or branched alkyl chain containing at least one triple bond. The term “alkoxy” refers to —O-alkyl, wherein alkyl is as defined above.

  The term “cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl ring consisting of 3 to 8 hydrogen-substituted carbon atoms. Examples include but are not limited to cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.

  The term “heterocyclyl” has 5 members, at least one of which is an N, O or S atom and optionally one additional O atom or 1, 2 or 3 additions A saturated or partially unsaturated ring which can contain 5 N atoms; a saturated or partially unsaturated ring having 6 members, of which 1, 2 or 3 members are N atoms Saturated or partially having 9 members, at least one of which is an N, O or S atom, and may optionally contain 1, 2 or 3 additional N atoms; Unsaturated bicyclic ring; and refers to a saturated or partially unsaturated bicyclic ring having 10 members, of which 1, 2 or 3 members are N atoms. Examples include, but are not limited to, pyrrolinyl, pyrrolidinyl, dioxolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl or piperazinyl.

  The term “aryl” refers to an aromatic monocyclic ring system containing 6 hydrogen-substituted carbon atoms, an aromatic bicyclic ring system containing 10 hydrogen-substituted carbon atoms, or 14 hydrogen-substituted carbon atoms. Refers to an aromatic tricyclic ring system containing Examples include but are not limited to phenyl, naphthalenyl or anthracenyl.

  The term “heteroaryl” contains 5 members, at least one member of which is an N, O or S atom and optionally contains 1, 2 or 3 additional N atoms. An aromatic monocyclic ring system having 6 members, of which 1, 2 or 3 members are N atoms, having 9 members, at least one of which An aromatic bicyclic ring in which the members are N, O or S atoms and optionally contain 1, 2 or 3 additional N atoms, as well as 10 members, Refers to an aromatic bicyclic ring in which 2 or 3 members are N atoms. Examples include but are not limited to furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl, quinolinyl or isoquinolinyl.

  The term “halo” or “halogen” refers to a fluoro, chloro, bromo or iodo atom.

  Where a particular group is “substituted” (eg, Ph, aryl, heteroalkyl, heteroaryl), the group is one or more substituents independently selected from the list of substituents, preferably 1 It can have ˜5 substituents, more preferably 1 to 3 substituents, most preferably 1 to 2 substituents.

  When referring to a substituent, the term “independently” means that where more than one such substituent is possible, such substituents can be the same or different from each other.

Under standard nomenclature used throughout this disclosure, the terminal portion of the side chain shown is first described, followed by adjacent functional groups towards the point of attachment. Thus, for example, a “phenyl C ₁ -C ₆ alkylaminocarbonyl C ₁ -C ₆ alkyl” substituent has the formula

Refers to the group of

Abbreviations used in the specification, particularly in the schemes and examples, are as follows:
DIPEA or DIEA = diisopropylethylamine DMA = dimethylacetamide DME = 1,2-dimethoxyethane DMF = N, N-dimethylformamide DMSO = dimethylsulfoxide DPCCI = diphenylcyanocarboimidate HPLC = high pressure liquid chromatography IPA = isopropyl alcohol MeCN = acetonitrile MeOH = methanol MTBE = methyl-t-butyl ether NMP = N-methylpyrrolidone Ph = phenyl Pyr = pyridine TEA = triethylamine THF = tetrahydrofuran As used herein, the term “patient” is the subject of treatment, observation or experiment. Animal, preferably mammal, most preferably human.

  As used herein, the term “therapeutically effective amount” refers to a tissue system, animal that is being sought by a researcher, veterinarian, physician, or other clinician that includes a reduction in the symptoms of the disease or disorder being treated. Or the amount of active compound or drug that elicits a biological or medical response in humans.

  As used herein, the term “composition” refers to any product that results directly or indirectly from a defined component in a defined amount and a combination of defined components in a defined amount. It is intended to encompass the product comprising.

  The present invention relates to a process for the preparation of compounds of formula (I) which are more fully described in the scheme below.

  Compounds of formula (I) can be prepared according to the method outlined in Scheme 1.

Accordingly, an appropriately substituted compound of formula (II), which is a known compound or a compound prepared by a known method, and a known compound, diphenylcyanocarboimidate;
Optionally a Lewis acid catalyst such as ZnCl ₂ , TiCl ₄ , SnCl ₄ , BF ₃ etherate or the like, or a first inorganic or organic base such as Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , Cs ₂ CO ₃ , NaOH , KOH, TEA, DIPEA, NaO (C _1-4 alkyl) (eg NaOCH ₂ CH ₃ , NaOCH ₃ , NaOC (CH ₃ ) ₃ etc.), KO (C _1-4 alkyl) (eg KO-tert-butyl etc.) ), Pyridine, etc., more preferably a first organic base, even more preferably a tertiary amine base such as TEA, DIPEA, pyridine, etc., even more preferably in the presence of pyridine;
A first organic solvent such as methanol, ethanol, IPA, n-butanol, tert-butanol, acetonitrile, pyridine, THF, IPA, DMF, DME, DMA, sulfolane, preferably in pyridine;
Preferably at a temperature in the range of about room temperature to about 120 ° C .;
More preferably in pyridine, at about room temperature;
React to give the corresponding compound of formula (III).

A suitably substituted compound of formula (IV) which is a known compound or a compound prepared by known methods;
Preferably a second organic or inorganic base, Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , Cs ₂ CO ₃ , NaOH, KOH, TEA, DIPEA, NaO (C _1-4 alkyl) (eg NaOCH ₂ CH ₃ , NaOCH ₃ , NaOC (CH ₃ ) ₃ ), KO (C _1-4 alkyl) (eg KO-tert-butyl etc.), pyridine, etc., more preferably a second organic base, even more preferably a tertiary In the presence of an amine base, such as TEA, DIPEA, pyridine, and even more preferably pyridine;
A second organic solvent such as methanol, ethanol, IPA, n-butanol, tert-butanol, acetonitrile, pyridine, THF, IPA, DMF, DME, DMA, sulfolane, preferably in pyridine;
Preferably at a temperature in the range of about room temperature to about 120 ° C .;
More preferably in pyridine at a temperature in the range of about 80 to about 90 ° C;
React to give the corresponding compound of formula (I).

  The present invention is further of formula (Ia) as outlined in Scheme 2 below.

It aims at the manufacturing method of this compound.

Therefore, the known compound 4-aminobenzenesulfonamide and the known compound diphenylcyanocarboimidate;
Optionally a Lewis acid catalyst such as ZnCl ₂ , TiCl ₄ , SnCl ₄ , BF ₃ etherate or the like, or a first inorganic or organic base such as Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , Cs ₂ CO ₃ , NaOH , KOH, TEA, DIPEA, NaO (C _1-4 alkyl) (eg NaOCH ₂ CH ₃ , NaOCH ₃ , NaOC (CH ₃ ) ₃ etc.), KO (C _1-4 alkyl) (eg KO-tert-butyl etc.) ), Pyridine, etc., more preferably a first organic base, even more preferably a tertiary amine base such as TEA, DIPEA, pyridine, etc., even more preferably in the presence of pyridine;
A first organic solvent such as methanol, ethanol, IPA, n-butanol, tert-butanol, acetonitrile, pyridine, THF, IPA, DMF, DME, DMA, sulfolane, preferably in pyridine;
Preferably at a temperature in the range of about room temperature to about 120 ° C .;
More preferably in pyridine, at about room temperature;
React to give the corresponding N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester.

N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester with 2,6-difluorobenzoic acid hydrazide which is a known compound;
Preferably a second organic or inorganic base, Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , Cs ₂ CO ₃ , NaOH, KOH, TEA, DIPEA, NaO (C _1-4 alkyl) (eg NaOCH ₂ CH ₃ , NaOCH ₃ , NaOC (CH ₃ ) ₃ ), KO (C _1-4 alkyl) (eg KO-tert-butyl etc.), pyridine, etc., more preferably a second organic base, even more preferably a tertiary In the presence of an amine base, such as TEA, DIPEA, pyridine, and even more preferably pyridine;
A second organic solvent such as methanol, ethanol, IPA, n-butanol, tert-butanol, acetonitrile, pyridine, THF, IPA, DMF, DME, DMA, sulfolane, preferably in pyridine;
Preferably at a temperature in the range of about room temperature to about 120 ° C .;
More preferably in pyridine at a temperature in the range of about 80 to about 90 ° C;
React to give the corresponding compound of formula (Ia).

  If the compounds according to the invention have at least one chiral center, they can therefore exist as enantiomers. If the compounds have two or more chiral centers, they can also exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. In addition, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are intended to be included within the scope of the present invention. Has been.

  If the process for the preparation of the compounds according to the invention results in a mixture of stereoisomers, these isomers can be separated by conventional methods, for example preparative chromatography. The compounds can be prepared in racemic form or the individual enantiomers can be prepared by enantiospecific synthesis or resolution. For example, dialysis by standard methods such as salt formation with optically active acids such as (−)-di-p-toluoyl-D-tartaric acid and / or (+)-di-p-toluoyl-L-tartaric acid. Compounds can be resolved into their component enantiomers by formation of stereomeric pairs and subsequent fractional crystallization and regeneration of the free base. Compounds can also be resolved by formation of diastereomeric esters or amides and subsequent chromatographic separation and removal of chiral auxiliaries. Alternatively, compounds can be resolved using chiral HPLC columns.

During the process for preparing the compounds of the invention, it may be necessary and / or desirable to protect sensitive or reactive groups (eg aldehydes, ketones, etc.) on any of the relevant molecules. Conventional protecting groups, such as Protective Groups in Organic Chemistry , ed. J. et al. F. W. McOmie, Plenum Press, 1973; W. Greene & P. G. M.M. This can be done according to what is described in Wuts, Protective Groups in Organic Synthesis , John Wiley & Sons, 1991. The protecting group can be removed at a subsequent convenient stage using methods known from the art.

  The method of the present invention was used in the preparation of representative compounds of formula (I) listed in Tables 1 and 2 below.

  The present invention is further directed to a novel crystalline form of the compound of formula (Ia). More specifically, the present invention is directed to two novel crystalline forms of the compound of formula (Ia), referred to below as phases (Ia-1) and (Ia-2).

The present invention is further directed to novel salt forms of the compounds of formula (Ia). In one embodiment, the present invention is directed to a novel crystalline salt of a compound of formula (Ia). More specifically, the novel crystalline salts of the compound of formula (Ia) are the CH ₂ SO ₃ H, HCl, HBr and H ₂ SO ₄ salts of the compound of formula (Ia).

The crystalline form of the compound of formula (Ia) and the crystalline salt of the compound of formula (Ia) can be characterized by their respective powder X-ray diffraction patterns. Unless otherwise noted, powder X-ray diffraction patterns were measured using a Phillips X'PERT PRO MPD Diffractometer. The sample was back-loaded into a normal X-ray holder. Using X-Celerator detector, scanning the specimen to 3 to 35 ^o 2 [Theta] at 0.0170 ^o 2 [Theta] step size and 10.16 seconds per step of the. The effective scanning speed was 0.2067 ^o / sec. Instrument voltage and current settings of 45 kV and 40 mA were used. The instrument tolerance 2Θ (2 theta) was 0.03 ^o 2Θ. Peaks with relative intensity <5% were not tabulated.

  In one embodiment of the present invention is a novel crystalline form of the compound of formula (Ia), hereinafter referred to as phase (Ia-1). The novel crystalline form (Ia-1) is obtained according to the method outlined in Scheme 2 above, preferably in the absence of a catalyst, and N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid ester Can be produced without isolation.

  Alternatively, N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid ester is isolated and then reacted to give the compound of formula (Ia) as phase (Ia-1) and phase (Ia-2) Crystalline form (Ia-1) can be prepared according to the method outlined in Scheme 2 given as a mixture of A mixture of phase (Ia-1) and phase (Ia-2) is dissolved in an organic solvent such as THF and then reacted with hydrochloric acid in an amount equal to about 1 equivalent, preferably with concentrated hydrochloric acid, to give the formula (Ia ) As its corresponding HCl salt and is isolated. The HCl salt of the isolated compound of formula (Ia) is suspended in water. The suspension is stirred to a constant pH. When dissolved in water, the compound of formula (Ia) precipitates as phase (Ia-1).

  The novel crystalline form (Ia-1) can be characterized by its XRD peaks listed in Table XRD-1 below. The XRD-spectrum for the new crystal form (Ia-1) was manually analyzed to an instrument tolerance of 0.03 degrees 2-theta.

  In another aspect of the present invention, there is provided a compound of formula (Ia) characterized by a main X-ray diffraction peak having a relative intensity greater than or equal to about 10% listed in Table XRD-1 above. There are new crystal forms. In another aspect of the present invention, there is provided a compound of formula (Ia) characterized by a principal X-ray diffraction peak having a relative intensity greater than or equal to about 20% listed in Table XRD-1 above. There are new crystal forms.

  The new crystalline form (Ia-1) can instead be characterized by its differential scanning calorimetry (DSC) melting endotherm, which exhibits a peak temperature at about 242 ° C. DSC melting endotherm was performed on a TA-Instruments Q1000 MTDSC instrument equipped with an RCS chiller by placing 3 mg of sample in a standard aluminum TA-Instrument sample pan and using a nitrogen purge of 50 mL / min. Measured by scanning at a heating rate of minutes.

In one embodiment of the present invention is a novel crystalline form of the compound of formula (Ia), hereinafter referred to as phase (Ia-2). A new crystalline form (Ia-2) is obtained by reacting 4-aminobenzenesulfonamide in the presence of ZnCl ₂ as a Lewis acid catalyst and N- [4- (aminosulfonyl)
Phenyl} -N′-cyanocarbamic acid phenyl ester can be prepared prior to reaction with 2,6-difluorobenzoic acid hydrazide and prepared according to the method outlined in Scheme 2 to give compounds of formula (Ia) .

  The novel crystalline form (Ia-2) can be characterized by its X-ray powder diffraction pattern listed in Table XRD-2 below.

Another aspect of the invention is a compound of formula (Ia) characterized by a main X-ray diffraction peak having a relative intensity greater than or equal to about 10% listed in Table XRD-2 above. There are new crystal forms. In another aspect of the present invention, there is provided a compound of formula (Ia) characterized by a principal X-ray diffraction peak having a relative intensity greater than or equal to about 20% listed in Table XRD-2 above. There are new crystal forms.

One aspect of the present invention is a novel crystalline CH ₃ SO ₃ H (methanesulfonyl) salt of the compound of formula (Ia). Another aspect of the present invention is a novel crystalline CH ₃ SO ₃ H salt of a compound of formula (Ia) wherein the molar ratio of the compound of formula (Ia) to CH ₃ SO ₃ H is 1: 1.

The CH ₃ SO ₃ H salt of the compound of formula (Ia) comprises CH ₃ SO ₃ H in an amount preferably equal to about 1 equivalent of the compound of formula (Ia) and the compound of formula (Ia) and CH ₃ SO ₃ H can dissolve, and non-reactive organic solvent to CH 3 _SO 3 _H, such as THF, dioxane, alcohols (e.g. methanol, ethanol, etc.) in such, preferably reacted in a temperature equal to that or roughly below room Can be manufactured.

The novel crystalline CH ₃ SO ₃ H salt of the compound of formula (Ia) can be characterized by its X-ray diffraction pattern listed in Table XRD-3 below.

In another aspect of the present invention, there is provided a compound of formula (Ia) characterized by a main X-ray diffraction peak having a relative intensity greater than or equal to about 10% listed in Table XRD-3 above. There is a new crystalline CH ₃ SO ₃ H salt. In another aspect of the present invention, there is provided a compound of formula (Ia) characterized by a principal X-ray diffraction peak having a relative intensity greater than or equal to about 20% as listed in Table XRD-3 above. There is a new crystalline CH ₃ SO ₃ H salt.

In one embodiment of the present invention is a novel crystalline HCl (hydrochloric acid) salt of the compound of formula (Ia). Another aspect of the invention is a novel crystalline HCl salt of a compound of formula (Ia) wherein the molar ratio of compound of formula (Ia) to HCl is 1: 1.

  The HCl salt of the compound of formula (Ia) is an organic salt which can dissolve the compound of formula (Ia) and HCl, preferably in an amount equal to about 1 equivalent, and the compound of formula (Ia) and HCl, and is non-reactive with HCl. It can be produced by reacting in a solvent such as THF, dioxane, alcohol (eg, methanol, ethanol, etc.), preferably at a temperature approximately lower than or equal to room temperature.

  The novel crystalline HCl salt of the compound of formula (Ia) can be characterized by its X-ray diffraction pattern listed in Table XRD-4 below.

  In yet another aspect of the present invention, compounds of formula (Ia) characterized by a principal X-ray diffraction peak having a relative intensity greater than or equal to about 10% listed in Table XRD-4 above There is a novel crystalline HCl salt. In yet another aspect of the present invention, compounds of formula (Ia) characterized by a principal X-ray diffraction peak having a relative intensity greater than or equal to about 20% listed in Table XRD-4 above There is a novel crystalline HCl salt.

One embodiment of the present invention is a novel crystalline HBr (hydrobromic acid) salt of the compound of formula (Ia). In another embodiment of the present invention, the compound of formula (Ia) to HBr has a molar ratio of 1: 1 (
There are new crystalline HBr salts of compounds of Ia).

  The HBr salt of the compound of formula (Ia) is an organic compound capable of dissolving the compound of formula (Ia), preferably HBr in an amount equal to about 1 equivalent, the compound of formula (Ia) and HBr, and non-reactive with HBr. It can be produced by reacting in a solvent such as THF, dioxane, alcohol (eg, methanol, ethanol, etc.), preferably at a temperature approximately lower than or equal to room temperature.

  The novel crystalline HBr salt of the compound of formula (Ia) can be characterized by its X-ray diffraction pattern listed in Table XRD-5 below.

  In yet another aspect of the present invention, compounds of formula (Ia) characterized by a principal X-ray diffraction peak having a relative intensity greater than or equal to about 10% listed in Table XRD-5 above There are new crystalline HBr salts. In yet another aspect of the present invention, a compound of formula (Ia) characterized by a principal X-ray diffraction peak having a relative intensity greater than or equal to about 20% listed in Table XRD-5 above There are new crystalline HBr salts.

One embodiment of the present invention is a novel crystalline H ₂ SO ₄ (sulfuric acid) salt of the compound of formula (Ia). Another aspect of the present invention is a novel crystalline H ₂ SO ₄ salt of a compound of formula (Ia) wherein the molar ratio of the compound of formula (Ia) to H ₂ SO ₄ is 1: 0.5.

The H ₂ SO ₄ salt of the compound of formula (Ia) can dissolve the compound of formula (Ia), preferably H ₂ SO ₄ in an amount equal to about 1 equivalent, the compound of formula (Ia) and H ₂ SO _4. And by reacting with H ₂ SO ₄ in a non-reactive organic solvent such as THF, dioxane, alcohol (eg, methanol, ethanol, etc.), preferably at a temperature approximately lower than or equal to room temperature. Can do.

The novel crystalline H ₂ SO ₄ salt of the compound of Formula (Ia), can be characterized by its X- ray diffraction pattern listed in Table XRD-6 below.

In yet another aspect of the present invention, compounds of formula (Ia) characterized by a principal X-ray diffraction peak having a relative intensity greater than or equal to about 10% listed in Table XRD-6 above There is a novel crystalline H ₂ SO ₄ salt. In yet another aspect of the present invention, compounds of formula (Ia) characterized by a principal X-ray diffraction peak having a relative intensity greater than or equal to about 20% listed in Table XRD-6 above There is a novel crystalline H ₂ SO ₄ salt.

  The following examples are presented to aid the understanding of the present invention and are in no way intended to limit the invention as set forth in the appended claims, and should not be considered as limiting.

N ³ -[(4-aminosulfonyl) phenyl] -1- (2′-thienoyl) -1H-1,2,4-triazole-3,5-diamine
(Compound No. 18)
In a clean dry reaction tube, 2-thiophenecarboxylic acid hydrazide (0.5951 g, 4.06 mmol), N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (1.2917 g, 4. 00 mmol) and pyridine (10 mL) were charged sequentially. The reaction mixture was heated to 85 ° C. and stirred for 22 hours. After 3 hours, a yellow solid precipitated. After 22 hours, the reaction mixture was cooled to 0 ° C. The precipitated solid was isolated by filtration, washed with H ₂ O (15 mL), dried in a vacuum oven at 60 ° C. for about 48 hours, and N ³ -[(4-aminosulfonyl) phenyl] -1- (2 ′ -Thienoyl) -1H-1,2,4-triazole-3,5-diamine was provided as a cream colored solid.

Melting point = 283.0-287.0 ° C. (decomposition)
MS: [M + H] ⁺ = 365, [M + Na] ⁺ = 387, [2M + Na] ⁺ = 751
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.15 (2H, s), 7.34 (1H, dd), 7.80 (4H, s), 7.91 (2H, br s), 8.21 (1H, dd), 8.31 (1H, dd), 9.93 (1H, s)
_{C 13 H 12 N 6 O 2} S 2; molecular weight = 364.41 elemental analysis:
Calculated: C, 42.85; H, 3.32; N, 23.06; S, 17.60
Measurement: C, 43.32; H, 3.12; N, 22.68; S, 17.23

N ³ -[(4-aminosulfonyl) phenyl] -1- (2′-furoyl) -1H-1,2,4-triazole-3,5-diamine
(Compound No. 17)
To a clean dry reaction tube was added 2-furoic acid hydrazide (0.5214 g, 4.05 mmol), N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (1.2919 g, 4.00). Mmol) and pyridine (10 mL) were charged in turn to give a slightly turbid pale yellow solution. The reaction mixture was heated to 85 ° C. and stirred for 21.25 hours. The reaction mixture was then cooled to room temperature and added dropwise to a mixture of vigorously stirred ice -H 2 _O of about 300 mL. A pale yellow solid precipitated. The suspension was stirred for 20 minutes. The solid product was filtered and washed sequentially with IPA (about 50 mL) and MTBE (about 50 mL). The product was dried in a vacuum oven at 90 ° C. for 10 hours and N ³ -[(4-aminosulfonyl) phenyl] -1- (2′-furanoyl) -1H-1,2,4-triazole-3,5 -The diamine was provided as a cream colored solid.

Melting point => 300 ° C
MS: [M + H] ⁺ = 349, [M + Na] ⁺ = 371, [2M + Na] ⁺ = 719
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 6.88 (1H, dd), 7.15 (2H, s), 7.68 (2H, d), 7.76 (2H, d), 7 .87 (2H, br s), 8.03 (1H, d), 8.18 (1H, s), 9.86 (1H, s)
_{C 13 H 12 N 6 O 4} S; - molecular weight = 348.34- about Elemental analysis:
Calculated: C, 44.82; H, 3.47; N, 24.13; S, 9.21
Measurement: C, 44.62; H, 3.34; N, 23.89; S, 9.13

N ³ -[(4-Aminosulfonyl) phenyl] -1- (2′-methoxybenzoyl) -1H-1,2,4-triazole-3,5-diamine (Compound No. 3)
In a clean dry reaction tube, 2-methoxybenzoic hydrazide (0.6864 g, 4.05 mmol), N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (1.2913 g, 4.05 mmol). 00 mmol) and pyridine (10 mL) were charged in turn to give a slightly cloudy cream colored solution. The reaction mixture was heated to 85 ° C. and stirred. After 6.5 hours, the reaction was complete, as judged by HPLC analysis, and the mixture was cooled to room temperature and added dropwise to about 300 mL of a vigorously stirred ice-H ₂ O mixture. A white solid precipitated. The suspension was stirred for 30 minutes. The solid product was filtered, washed with H ₂ O (2 × 30 mL) and dried in a vacuum oven at 80 ° C. for 10 hours. The crude product at room temperature _CH 3 CN (about 15-20 mL) was suspended in, filtered and dried to ^N 3 - [(4-aminosulfonyl) phenyl] -1- (2'-methoxybenzoyl) - 1H-1,2,4-triazole-3,5-diamine was provided as a white solid.

Melting point 217.0-221.5 ° C.
MS: [M + H] ⁺ = 389, [M + Na] ⁺ = 411, [2M + Na] ⁺ = 799
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 3.78 (3H, s), 7.07 (2H, s), 7.07 (1H, m), 7.20 (1H, dd), 7 .48 (3H, m), 7.55 (3H, m), 7.80 (2H, br s), 9.70 (1H, s)
_{C 16 H 16 N 6 O 4} Sx0.09H 2 O; - molecular weight = 390.03- about Elemental analysis:
Calculated: C, 49.28; H, 4.18 ; N, 21.55; S, 8.22; H 2 O, 0.42
Measurement: C, 49.00; H, 3.72; N, 21.59; S, 8.33; H ₂ O, 0.40

N ³ -[(4-aminosulfonyl) phenyl] -1- (4′-hydroxybenzoyl) -1H-1,2,4-triazole-3,5-diamine (Compound No. 10)
In a clean dry reaction tube, 4-hydroxybenzoic acid hydrazide (0.6285 g, 4.05 mmol), N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (1.2915 g, 4.05 mmol). 00 mmol) and pyridine (10 mL) were charged in turn to give a white suspension. The reaction mixture was heated to 85 ° C. by which time a solution had formed. After 20 hours, the reaction was cooled to room temperature and then added dropwise to about 300 mL of a vigorously stirred ice-H ₂ O mixture. A white solid precipitated. The suspension was stirred for 20-30 minutes. The solid product was filtered and washed sequentially with H ₂ O (about 100 mL), IPA (about 50 mL) and MTBE (about 50 mL). The precipitated solid in the filtrate was recovered, combined with the product, dried in a vacuum oven at 65 ° C. for 10 hours, and N ³ -[(4-aminosulfonyl) phenyl] -1- (4′-hydroxybenzoyl) -1H -1,2,4-Triazole-3,5-diamine was provided as a snow white solid.

Melting point> 300 ° C
MS: [M + H] ⁺ = 375, [M + Na] ⁺ = 397
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 6.92 (2H, d), 7.12 (2H, s), 7.67 (4H, m), 7.79 (2H, br s), 8.17 (2H, d), 9.76 (1H, s), 10.45 (1H, br s)
_{C 15 H 14 N 6 O 4} S; molecular weight = 374.38 elemental analysis:
Calculated: C, 48.12; H, 3.77; N, 22.45; S, 8.57
Measurement: C, 48.06; H, 3.52; N, 22.09; S, 8.44

N ³ -[(4-Aminosulfonyl) phenyl] -1- (2′-chlorobenzoyl) -1H-1,2,4-triazole-3,5-diamine
(Compound No. 2)
In a clean dry reaction tube, 2-chlorobenzoic acid hydrazide (0.7053 g, 4.05 mmol), N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (1.2910 g, 4.05). 00 mmol) and pyridine (10 mL) in turn gave a slightly cloudy, pale yellow solution. The reaction mixture was heated to 85 ° C. by which time a solution had formed. After 20 hours, the reaction mixture was cooled to room temperature and then added dropwise to a mixture of vigorously stirred ice -H 2 _O of about 300 mL. A white solid precipitated. The suspension was stirred for 20-30 minutes. The solid product was filtered and washed sequentially with H ₂ O (about 100 mL), IPA (about 50 mL) and MTBE (about 50 mL). The precipitated solid in the filtrate was collected, combined with the product, dried in a vacuum oven at 65 ° C. for 10 hours, and N ³ -[(4-aminosulfonyl) phenyl] -1- (2′-chlorobenzoyl) -1H -1,2,4-Triazole-3,5-diamine was provided as a snow white solid.

Melting point = 237.0-242.5 ° C.
MS: [M + H] ⁺ = 393, [M + Na] ⁺ = 415
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.07 (2H, s), 7.46 (2H, d), 7.51-7.64 (3H, m), 7.55 (2H, d), 7.70 (1H, dd), 7.93 (2H, br s), 9.77 (1H, s)
Elemental analysis for C ₁₅ H ₁₃ ClN ₆ O ₃ S; molecular weight = 392.83:
Calculated: C, 45.86; H, 3.34; N, 21.39; S, 8.16; Cl, 9.03
Measurement: C, 45.63; H, 3.07; N, 21.19; S, 8.18; Cl, 8.87

N ³ -[(4-Aminosulfonyl) phenyl] -1- (2′-bromobenzoyl) -1H-1,2,4-triazole-3,5-diamine
(Compound No. 4)
In a clean dry reaction tube, 2-bromobenzoic hydrazide (1.48 g, 6.88 mmol), N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (2.0 g, 6. 33 mmol) and pyridine (20 mL) were charged sequentially to give a white suspension. The reaction mixture was heated to 85 ° C. by which time a solution had formed. After 6 hours, the reaction mixture was cooled to room temperature and then added dropwise to approximately 275 mL of a vigorously stirred mixture of 250 mL NH ₄ Cl solution and 25 mL MeOH. A white solid precipitated. The suspension was stirred for 20-30 minutes. The solid product was filtered and washed with H ₂ O (ca. 20 mL). The product was dried in a vacuum oven at 60-65 ° C. for 12 hours. The crude product was suspended in methanol (60 mL) and stirred overnight at room temperature. The product was filtered, washed with methanol (10 mL), dried in a vacuum oven at 60 ° C., and N ³ -[(4-aminosulfonyl) phenyl] -1- (2′-bromobenzoyl) -1H-1 2,4-triazole-3,5-diamine was obtained as a white solid.

HPLC purity: 99.4 A%
Melting point = 246-248 ° C.
MS: [M + H] ⁺ = 438.9, [M + Na] ⁺ = 460.9
¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.09 (2H, s), 7.46 (2H, d), 7.47 (2H, m), 7.49 (2H, d), 7 .67 (1H, dd
), 7.76 (1H, dd), 7.94 (2H, br s), 9.79 (1H, s)
_{C 15 H 13 BrN 6 O 3} S; molecular weight = 437.3 elemental analysis:
Calculated values: C, 41.20; H, 3.00; N, 19.22; S, 7.33; Br, 18.27
Measurement: C, 41.44; H, 2.94; N, 19.06; S, 7.24; Br, 18.44

N ³ -[(4-Aminosulfonyl) phenyl] -1- (3′-bromobenzoyl) -1H-1,2,4-triazole-3,5-diamine
(Compound No. 7)
In a clean dry reaction tube, 3-bromobenzoic acid hydrazide (1.48 g, 6.88 mmol), N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (2.0 g, 6. 33 mmol) and pyridine (20 mL) were charged sequentially to give a white suspension. The reaction mixture was heated to 85 ° C. by which time a solution had formed. After 6 hours, the reaction mixture was cooled to room temperature and then added dropwise to approximately 275 mL of a vigorously stirred mixture of 250 mL NH ₄ Cl solution and 25 mL MeOH. A white solid precipitated. The suspension was stirred for 20 to 30 minutes, the solid product was _filtered, washed with _H 2 O (about 20 mL). The product was dried in a vacuum oven at 60-65 ° C. for 12 hours. It was purified by suspending the crude product in methanol (100 mL) and refluxing after which time the suspension was cooled to 20-25 ° C. and filtered. The process was then repeated and the product was washed with methanol (10 mL), dried in a vacuum oven at 70 ° C. for 48 hours, and N ³ -[(4-aminosulfonyl) phenyl] -1- (3′-bromobenzoyl) ) -1H-1,2,4-triazole-3,5-diamine was provided as a white solid.

HPLC purity: 99.6 A%
Melting point = 242-244 ° C.
MS: [M + H] ⁺ = 438.9
¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.15 (2H, s), 7.56 (1H, m), 7.66 (4H, m), 7.91-7.92 (3H, m), 8.04 (1H, d), 8.49 (1H, s), 9.86 (1H, s)
_{C 15 H 13 BrN 6 O 3} S; molecular weight = 437.3 elemental analysis:
Calculated values: C, 41.20; H, 3.00; N, 19.20; S, 7.33; Br, 18.27
Measurement: C, 41.44; H, 2.92; N, 19.07; S, 7.24; Br, 18.42

N ³ -[(4-aminosulfonyl) phenyl] -1- (benzoyl) -1H-1,2,4-triazole-3,5-diamine
(Compound No. 1)
To a clean dry reaction tube, benzoic hydrazide (0.94 g, 6.88 mmol), N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (2.0 g, 6.33 mmol). And pyridine (20 mL) were charged sequentially to give a white suspension. The reaction mixture was heated to 85 ° C. by which time a solution had formed. After 6 hours, the reaction mixture was cooled to room temperature and then added dropwise to approximately 275 mL of a vigorously stirred mixture of 250 mL NH ₄ Cl solution and 25 mL MeOH. A white solid precipitated. The suspension was stirred for 20 to 30 minutes, the solid product was _filtered, washed with _H 2 O (about 20 mL). The solid product was dried in a vacuum oven at 60-65 ° C. for 12 hours. The crude product was suspended in methanol (180 mL) and stirred overnight. The product was filtered, washed with methanol (10 mL), dried in a vacuum oven at 70 ° C. overnight, N ³ -[(4-aminosulfonyl) phenyl] -1- (benzoyl) -1H-1,2, 4-Triazole-3,5-diamine was provided as a white solid. HPLC purity: 99.4 A%
354-356 ° C
MS: [M + H] ⁺ = 359.0, [M + Na] ⁺ = 381.0
¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.12 (2H, s), 7.56-7.68 (7H, m), 7.89 (2H, br s), 8.14 (2H , M), 9.80 (1H, s)
_{C 15 H 14 N 6 O 3} S; molecular weight = 358.4 Elemental Analysis Calculated for: C, 50.27; H, 3.94 ; N, 23.45; S, 8.95
Measurements: C, 50.24; H, 3.95; N, 23.58; S, 9.05

N ³ -[(4-aminosulfonyl) phenyl] -1- (3′-nitrobenzoyl) -1H-1,2,4-triazole-3,5-diamine
(Compound No. 5)
In a clean dry reaction tube, 3-nitrobenzoic acid hydrazide (1.26 g, 6.88 mmol), N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (2.0 g, 6. 33 mmol) and pyridine (20 mL) were charged in sequence to give a light yellow suspension. The reaction mixture was heated to 85 ° C. by which time a solution had formed. After 6 hours, the reaction mixture was cooled to room temperature and then added dropwise to approximately 275 mL of a vigorously stirred mixture of 250 mL NH ₄ Cl solution and 25 mL MeOH. A light yellow solid precipitated. The suspension was stirred for 20 to 30 minutes, the solid product was _filtered, washed with _H 2 O (about 20 mL). It was purified by suspending the crude product in a mixture of 150 mL CH ₃ CN (150 mL) and THF (15 mL) at 60-70 ° C. The suspension was cooled to 20-25 ° C. and filtered. The purification procedure was then repeated and the solid was washed with CH ₃ CN (20 mL), dried in a vacuum oven at 60 ° C. for 48 hours, and N ³ -[(4-aminosulfonyl) phenyl] -1- (3′- Nitrobenzoyl) -1H-1,2,4-triazole-3,5-diamine was provided as a light yellow solid.

HPLC purity: 99.5 A%
Melting point 260-262 ° C
MS: [M + H] ⁺ = 404.0; [M + Na] ⁺ = 426.0
¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.17 (2H, s), 7.68 (4H, br s), 7.88 (1H, t), 7.97 (2H, br s) , 8.50 (2H, m), 9.28 (1H, s), 9.88 (1H, s)
_{C 15 H 13 N 7 O 5} S; molecular weight = 403.4 elemental analysis:
Calculated: C, 44.66; H, 3.25; N, 24.31; S, 7.95
Measurement: C, 44.39; H, 3.26; N, 24.25; S, 8.03

N ³ -[(4-Aminosulfonyl) phenyl] -1- (4′-nitrobenzoyl) -1H-1,2,4-triazole-3,5-diamine
(Compound No. 9)
To a clean dry reaction tube was added 4-nitrobenzoic acid hydrazide (1.26 g, 6.88 mmol), N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (2.0 g, 6. 33 mmol) and pyridine (20 mL) were charged in turn to give a yellow suspension. The reaction mixture was heated to 85 ° C. by which time a solution had formed. After 6 hours, the reaction was cooled to room temperature and then added dropwise to approximately 275 mL of a vigorously stirred mixture of 250 mL NH ₄ Cl solution and 25 mL MeOH. A yellow solid precipitated. The suspension was stirred for 20 to 30 minutes, the solid product was _filtered, washed with _H 2 O (about 20 mL). The product was dried in a vacuum oven at 60-65 ° C. for 12 hours. The crude product was suspended in refluxing THF (50 mL). The suspension was cooled to 20-25 ° C. and filtered. The solid was dried in a vacuum oven at 60 ° C. overnight and N ³ -[(4-aminosulfonyl) phenyl] -1- (4′-nitrobenzoyl) -1H-1,2,4-triazole-3,5- The diamine was given as a light yellow solid.

HPLC purity: 96.8 A%
Melting point: 336-338 ° C
MS: [M + H] ⁺ = 404.0; [M + Na] ⁺ = 426.0
¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.12 (2H, s), 7.58 (2H, d), 7.69 (2H, d), 7.97 (2H, br s), 8.31 (2H, d), 8.42 (2H, d), 9.85 (1H, s)
_{C 15 H 13 N 7 O 5} S; molecular weight = 403.4 elemental analysis:
Calculated: C, 44.66; H, 3.25; N, 24.31; S, 7.95
Measurements: C, 44.56; H, 3.30; N, 24.34; S, 7.57

N ³ -[(4-Aminosulfonyl) phenyl] -1-acetyl-1H-1,2,4-triazole-3,5-diamine
(Compound No. 16)
In a clean dry reaction tube, acetic hydrazide (0.52 g, 6.88 mmol), N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (2.0 g, 6.33 mmol) and Pyridine (20 mL) was charged sequentially to give a white suspension. The reaction mixture was heated to 85 ° C. by which time a solution had formed. After 6 hours, the reaction mixture was cooled to room temperature and then added dropwise to approximately 275 mL of a vigorously stirred mixture of 250 mL NH ₄ Cl solution and 25 mL MeOH. A white solid precipitated. The suspension was stirred for 20 to 30 minutes, the solid product was _filtered, washed with _H 2 O (about 20 mL). The product was dried in a vacuum oven at 60-65 ° C. for 12 hours. The crude product was suspended in EtOH (60 mL) and stirred at 20-25 ° C. overnight. The product was filtered, washed with EtOH (10 mL), dried in a vacuum oven at 60 ° C. for 12 hours, and N ³ -[(4-aminosulfonyl) phenyl] -1- (acetyl) -1H-1,2 , 4-triazole-3,5-diamine was obtained as a white solid.

Melting point 334-336 ° C
MS: [M + H] ⁺ = 297.0
¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.52 (3H, s), 7.13 (2H, s), 7.62 (2H, br s), 7.69 (4H, s), 7.92 (s, 1H)
_{C 10 H 12 N 6 O 3} S; molecular weight = 296.3 elemental analysis:
Calculated values: C, 40.53; H, 4.08; N, 28.36; S, 10.82
Measurement: C, 40.35; H, 3.86; N, 28.25; S, 11.04

N ³ -[(4-aminosulfonyl) phenyl] -1- (4′-methoxybenzoyl) -1H-1,2,4-triazole-3,5-diamine (Compound No. 12)
In a clean dry reaction tube, 4-methoxybenzoic acid hydrazide (0.80 g, 4.73 mmol), N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (1.30 g, 4. 02 mmol) and pyridine (10 mL) were charged sequentially. After stirring at room temperature for 5-10 minutes, a solution formed, after which time the reaction mixture was heated to 85 ° C. and stirred at 85 ° C. for 3 hours. The reaction mixture was cooled to room temperature and then added dropwise to about 150 mL of a vigorously stirred ice-saturated NaCl solution mixture. A white solid precipitated. The suspension was stirred for 20-30 minutes and the solid product was filtered, washed with H ₂ O (about 100 mL) and dried in a vacuum oven at 60-65 ° C. for 12 hours. The crude product was suspended in MeOH (50 mL) and stirred at 20-25 ° C. overnight. The product was filtered, washed with MeOH (10 mL), dried in a vacuum oven at 70 ° C. for 12 hours and N ³ -[(4-aminosulfonyl) phenyl] -1- (4′-methoxybenzoyl) -1H -1,2,4-Triazole-3,5-diamine was provided as a white solid.

Melting point: 244.5-247.5 ° C
MS: [M + H] ⁺ = 389.0, [M + H] ⁺ = 411
¹ H NMR (300 MHz, DMSO-d ₆ ): δ 3.89 (3H, s), 7.13 (2H, s), 7.14 (2H, d), 7.64 (2H, d), 7 .71 (2H, d), 7.85 (2H, br s), 7.69 (4H, s), 8.25 (2H, d), 9.80 (s, 1H)
_{C 16 H 16 N 6 O 4} Sx0.1H 2 O; molecular weight = 390.2 elemental analysis:
Calculated: C, 49.25; H, 4.18 ; N, 21.54; S, 8.22; H 2 O, 0.46
Measurements: C, 48.92; H, 3.93 ; N, 21.34; S, 8.00; H 2 O, 0.51

N ³ -[(4-Aminosulfonyl) phenyl] -1- (4′-phenylbenzoyl) -1H-1,2,4-triazole-3,5-diamine (Compound No. 11)
In a clean dry reaction tube, 4-phenylbenzoic acid hydrazide (0.99 g, 4.65 mmol), N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (1.30 g, 4.65 g). 02 mmol) and pyridine (10 mL) were charged sequentially. After stirring at room temperature for 5-10 minutes, a solution formed, after which time the reaction mixture was heated to 85 ° C. and stirred at 85 ° C. for 3 hours. The reaction mixture was cooled to room temperature and a solid precipitated. The cream colored suspension was reheated to about 60 ° C. to give a solution which was then added dropwise to about 150 mL of a vigorously stirred ice-saturated NaCl solution mixture. A pale yellow solid precipitated. The suspension was stirred for 20 to 30 minutes, the solid product was _filtered, washed with _H 2 O (about 100 mL), then air dried. The crude product was dissolved in DMSO (5 mL) and purified on a silica gel column (30 g) with a mixture of ethyl acetate / n-heptane (80/20). Product containing fractions were combined and evaporated. The resulting solid was suspended in water (9 mL) and stirred at 55 ° C. for 2 hours. The suspension was then cooled to room temperature and filtered. The solid was washed with water (15 mL), dried in a vacuum oven for 36 hours at 90 ° C., and N ³ -[(4-aminosulfonyl) phenyl] -1- (4′-phenylbenzoyl) -1H-1,2 , 4-triazole-3,5-diamine was obtained as a white solid.

Melting point> 260 ° C
MS: [M + H] ⁺ = 435.0
¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.11 (2H, s), 7.46 (1H, t), 7.54 (2H, t), 7.66 (2H, d), 7 .71 (2H, d), 7.81 (2H, d), 7.91 (2H, d), 7.93 (2H, br s), 8.29 (2H, d), 9.83 (s) , 1H)
C ₂₁ H ₁₈ N ₆ O ₃ Sx0.55H ₂ O; Elemental analysis for molecular weight = 444.39 Calculated: C, 56.76; H, 4.33; N, 18.91; S, 7.22; ₂ O, 2.23
Measurements: C, 56.50; H, 4.16; N, 18.51; S, 7.23; H ₂ O, 2
. 31

N ³ -[(4-Aminosulfonyl) phenyl] -1- (4′-chlorobenzoyl) -1H-1,2,4-triazole-3,5-diamine
(Compound No. 28)
In a clean dry reaction tube, 4-chlorobenzoic acid hydrazide (0.83 g, 4.79 mmol), N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (1.30 g, 4.79 mmol). 02 mmol) and pyridine (10 mL) were charged sequentially. After stirring at room temperature for 5-10 minutes, a solution formed, after which time the reaction mixture was heated to 85 ° C. and stirred at 85 ° C. for 3 hours. The reaction mixture was cooled to room temperature and a solid precipitated. The yellow suspension was reheated to about 60 ° C. to give a solution which was then added dropwise to about 150 mL of a vigorously stirred ice-saturated NaCl solution mixture. A white solid precipitated. The suspension was stirred for 20 to 30 minutes, the solid product was _filtered, washed with _H 2 O (about 100 mL), then air dried. The crude product was dissolved in DMSO (5 mL) and purified on a silica gel column (35 g) with a mixture of ethyl acetate / n-heptane (80/20). Product containing fractions were combined and evaporated. The resulting oily solid-containing residual DMSO was suspended in water (10 mL) and stirred at 40 ° C. for 14 hours. The suspension was then cooled to room temperature and filtered. The solid was then washed with water (20 mL). The product was dried in a vacuum oven at 130 ° C. for 60 hours, and N ³ -[(4-aminosulfonyl) phenyl] -1- (4′-chlorobenzoyl) -1H-1,2,4-triazole-3, 5-diamine was provided as a white solid.

Melting point> 260 ° C
MS: [M + H] ⁺ = 393.0
¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.14 (2H, s), 7.62 (2H, d), 7.69 (4H, m), 7.92 (2H, br s), 8.19 (2H, d), 9.83 (s, 1H)
_{C 15 H 13 ClN 6 O 3} Sx0.25H 2 O; molecular weight = 397.33 Elemental analysis Calculated for: C, 45.34; H, 3.42 ; N, 21.15; S, 8.07; Cl , 8.92; H ₂ O, 1.13
Measurement: C, 45.44; H, 3.19 ; N, 20.45; S, 7.98; Cl, 9.39; H 2 O, 1.42

N ³ -Phenyl-1- (4′-methylbenzoyl) -1,2,4-triazole-3,5-diamine
(Compound No. 25)
A solution of aniline (0.3845 g, 4.10 mmol) and diphenylcyanocarboimidate (0.9830 g, 4.00 mmol) in pyridine (15 mL) was stirred at room temperature for 1 hour, at which point HPLC analysis was Showed that it was completed. 4-Methylbenzoic acid hydrazide (0.6074 g, 4.00 mmol) was added and the clear yellow solution was heated to 85 ° C. The reaction mixture was stirred at 85 ° C. for 9 hours, after which time the reaction mixture was cooled to room temperature and added dropwise to about 200 mL of a vigorously stirred ice-H ₂ O mixture. A white solid precipitated. The suspension was stirred for 1 hour and then filtered. The solid was washed with H ₂ O (about 100 mL) and then air dried for several hours. The crude product was suspended in MeOH (30 mL) and stirred at room temperature for several hours. The suspension was filtered and the solid was washed with MeOH and dried in a vacuum oven at 100 ° C. for 12 hours to give N ³ -phenyl-1- (4′-methylbenzoyl) -1,2,4-triazole-3. , 5-diamine was given as a white solid.

Melting point 222.5-224.0 ° C
MS: [M + H] ⁺ = 294, [M + Na] ⁺ = 317
¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.49 (3H, s), 6.85 (1H, br t), 7.23 (2H, br t), 7.38 (2H, d) 7.54 (2H, d), 7.82 (2H, br s), 8.13 (2H, d), 9.31 (s, 1H)
Elemental analysis for C ₁₆ H ₁₅ N ₅ O; molecular weight = 293.33:
Calculated value: C, 65.52; H, 5.15; N, 23.88
Measurement: C, 65.26; H, 5.03; N, 23.90

N ³ -Phenyl-1- (2′methoxybenzoyl) -1,2,4-triazole-3,5-diamine
(Compound No. 29)
A solution of aniline (0.3845 g, 4.10 mmol) and diphenylcyanocarboimidate (0.9817 g, 4.00 mmol) in pyridine (15 mL) was stirred at room temperature for 1 hour, at which point HPLC analysis was Showed that it was completed. 2-Methoxybenzoic acid hydrazide (0.6855 g, 4.00 mmol) was added and the resulting yellow solution was heated to 85 ° C. and stirred at 85 ° C. for 4 hours. After 4 hours, the reaction mixture was cooled to room temperature and added dropwise to about 200 mL of a vigorously stirred ice-H ₂ O mixture. A white solid precipitated. The suspension was stirred for 0.5 hours and then filtered. The solid was washed with H ₂ O (about 100 mL) and then air dried for 1 hour. The crude product was suspended in CH ₃ CN (5 mL) and stirred at room temperature overnight. The suspension is filtered and the solid is washed with CH ₃ CN and then dried in a vacuum oven at 70 ° C. for 5 hours to give N ³ -phenyl-1- (2′-methoxybenzoyl) -1,2,4- Triazole-3,5-diamine was provided as a white solid.

Melting point 89.5-94.0 ° C
MS: [M + H] ⁺ = 310, [M + Na] ⁺ = 332
¹ H NMR (300 MHz, DMSO-d ₆ ): δ 3.77 (3H, s), 6.77 (1H, t), 7.03-7.19 (2H, m), 7.09 (2H, d), 7.37 (2H, d), 7.45-7.55 (2H, m), 7.75 (2H, brs), 9.19 (s, 1H)
HRMS: for C ₁₆ H ₁₅ N ₅ O ₂ : calculated: 310.1299
Measurement: 310.1306

N ³ -Phenyl-1- (3′-methoxybenzoyl) -1,2,4-triazole-3,5-diamine
(Compound No. 30)
A solution of aniline (0.3845 g, 4.10 mmol) and diphenylcyanocarboimidate (0.9822 g, 4.00 mmol) in pyridine (15 mL) was stirred at room temperature for 1 hour, at which point HPLC analysis was Showed that it was completed. 3-Methoxybenzoic acid hydrazide (0.6794 g, 4.00 mmol) was added to give a light brown solution that was heated to 85 ° C. and stirred at 85 ° C. for 4 hours. After 4 hours, the reaction was cooled to room temperature and then added dropwise to about 200 mL of a vigorously stirred ice-H ₂ O mixture. A yellow solid precipitated. The suspension was stirred for 0.5 hours and then filtered. The solid was washed with H ₂ O (about 100 mL) and then air dried for 1 hour. The crude product was washed with CH ₃ CN (2 × 25 mL), MTBE (25 mL), and the product was dried in a vacuum oven at 40 ° C. for 12 hours to give N ³ -phenyl-1- (3′-methoxybenzoyl) -1 2,4-triazole-3,5-diamine was obtained as a pale yellow solid.

Melting point: 174-184 ° C
MS: [M + H] ⁺ = 310, [M + Na] ⁺ = 332
¹ H NMR (300 MHz, DMSO-d ₆ ): δ 3.85 (3H, s), 6.84 (1H, t), 7.18-7.25 (3H, m), 7.46-7. 55 (3H, m), 7.72 (1H, s), 7.84 (3H, br s), 9.34 (s, 1H)
HRMS: for C ₁₆ H ₁₅ N ₅ O ₂ : calculated: 310.1299
Measurement: 310.1302

N ³ -Phenyl-1- (2-furoyl) -1,2,4-triazole-3,5-diamine
(Compound No. 31)
A solution of aniline (0.3845 g, 4.10 mmol) and diphenylcyanocarboimidate (0.9825 g, 4.00 mmol) in pyridine (15 mL) was stirred at room temperature for 2 hours, at which time HPLC analysis showed no reaction. Showed that it was completed. 2-Furoic acid hydrazide (0.5144 g, 4.00 mmol) was added to give an amber colored solution that was heated to 85 ° C. and stirred at 85 ° C. for 23.5 hours. After 23.5 hours, the reaction mixture was cooled to room temperature and then added dropwise to about 200 mL of a vigorously stirred ice-H ₂ O mixture. A light brown solid precipitated. The suspension was stirred for 1 hour and then filtered. The solid was washed with H ₂ O (about 100 mL) and air dried for 1 hour. The crude product was recrystallized from CH ₃ CN / H ₂ O (1: 1), filtered and dried in a vacuum oven at 45 ° C. for 12 hours to give N ³ -phenyl-1- (2-furoyl) -1 2,4-triazole-3,5-diamine was provided as a cream colored solid.

Melting point 201.0-202.0 ° C
MS: [M + H] ⁺ = 270, [M + Na] ⁺ = 292
¹ H NMR (300 MHz, DMSO-d ₆ ): δ 6.86-6.92 (2H, m), 7.31 (2H, t), 7.57 (2H, d), 7.82 (2H, br s), 8.05 (1H, d), 8.17 (1H, d), 9.39 (s, 1H)
C ₁₃ H ₁₁ N ₅ O ₂ ; Elemental analysis for molecular weight = 269.26 Calculated: C, 57.99; H, 4.12; N, 26.01
Measurement: C, 58.01; H, 3.94; N, 25.91

N- [4- (Aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester Diphenylcyanocarboimidate (DPCCI) (10.0 g, 42.0 mmol) in THF (150 mL) at about 20-25 ° C. Was treated with 0.5M ZnCl ₂ (6.1 mL, 3.0 mmol) in THF. The flask containing the reaction mixture was sealed and the reaction mixture was stirred at about 20-25 ° C. overnight. After stirring overnight, 4-aminobenzenesulfonamide (7.2 g, 41.8 mmol) was added to the reaction mixture. The reaction mixture was then heated to reflux and held at this temperature for 10 hours with stirring. During this time a solid precipitated from the reaction mixture. After 10 hours, the reaction mixture was cooled to about 0-5 ° C., the solid was collected by filtration, washed with THF (20 mL), dried in a vacuum oven at about 60-70 ° C. overnight, and N- [4- ( Aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester was provided as a white solid.

Melting point> 250 ° C
[M + H] ⁺ = 317.0, [M + Na] ⁺ = 339.0
¹ H NMR (400 MHz, DMSO): δ 7.34 (5H, m), 7.46-7. (2H, m), 7.66 (2H, d), 7.85 (2H, d) ), 11.13 (1H, s)
Elemental analysis for C ₁₄ H ₁₂ N ₄ O ₃ S; molecular weight = 316.34:
Calculated values: C, 53.16; H, 3.82; N, 17.71; S, 10.14
Measurement: C, 52.39; H, 3.67; N, 17.32; S, 9.87
KF = 0.30% H ₂ O

Preparation of N- [4- (aminosulfonyl) phenyl] -N′- cyanocarbamic acid phenyl ester Diphenylcyanocarboimidate (DPCCI) (875.0 g, 3 .67 mol) was treated with 0.5 M ZnCl ₂ (510.0 mL, 0.255 mol) in THF. The flask containing the reaction mixture was sealed and the reaction mixture was stirred at about 20-25 ° C. overnight. After stirring overnight, 4-aminobenzenesulfonamide (668.0 g, 3.88 mol) was added to the reaction mixture, and then the reaction mixture was heated to reflux and held at reflux temperature for 10 hours with stirring. During this time a solid precipitated from the reaction mixture. After 10 hours, the reaction mixture was cooled to about 0-5 ° C., the solid was collected by filtration, washed with DME (700 mL), dried in a vacuum oven at about 50-70 ° C. overnight, and N- [4- ( Aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester was provided. This material was used in subsequent steps without further characterization.

HPLC purity: 93.7 A%, 93.4% by weight
KF 0.46% H ₂ O

A solution of 4-aminobenzenesulfonamide (850 g, 4.89 mol) in N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester pyridine (4.0 L) was stirred to diphenylcyano. Carboimidate (DPCCI) (600 g, 2.45 mol) was added and cooled in an ice bath. The mixture was stirred at <30 ° C. during which time the solid dissolved. A second portion of diphenylcyanocarboimidate (DPCCI) (600 g, 2.45 mol) was added followed by pyridine (0.77 L). The mixture was stirred at <30 ° C. during which time the solid dissolved. After 3.5 hours of stirring, the reaction was judged complete by HPLC analysis (<1% residual DPCCI), during which time the reaction mixture became a thick white suspension. Methyl tert-butyl ether (10.0 L) was then added to the reaction mixture and the suspension was stirred and cooled to about 0-5 ° C. The solid was isolated by filtration, washed with methyl tert-butyl ether (4.0 L), dried in a vacuum oven overnight at about 80 ° C./29.5 ″ and N- [4- (aminosulfonyl) phenyl] -N '-Cyanocarbamic acid phenyl ester was provided as a white solid.

HPLC purity: 96.4% by weight
[M + H] ⁺ = 317.0, [M + Na] ⁺ = 339.0
¹ H NMR (400 MHz, DMSO): δ 7.30-7.50 (5H, m), 7.65 (2H, d), 7.85 (2H, d), 11.14 (1H, s)
Elemental analysis for C ₁₄ H ₁₂ N ₄ O ₃ S; molecular weight = 316.34:
Calculated values: C, 53.16; H, 3.82; N, 17.71; S, 10.14
Measurement: C, 53.10; H, 3.65; N, 17.52; S, 9.86

N ³ -[(4-Aminosulfonyl) phenyl] -1- (2 ′, 6′-difluorobenzoyl) -1H-1,2,4-triazole-3,5-diamine (Compound (Ia))
N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (2.0 g, 6.33 mmol), 2,6-difluorobenzoyl hydrazide (1.2 g, 6.98 mmol) and DMF (10 mL) of the mixture was stirred at about 20-30 ° C. until a solution was obtained. The reaction mixture was then heated to 110 ° C. The reaction was judged complete by HPLC after 3.5 hours (<1% residual O-phenylisourea). The reaction mixture was cooled to about 20-30 ° C. and then quenched into water (100 mL). The crude solid was filtered, dissolved in a small volume of DMF (1 mL) and chromatographed on silica gel using EtOAc as eluent. Evaporation of the EtOAc ^fraction, N 3 - [(4-aminosulfonyl) - phenyl] -1- (2 ', 6'-difluorobenzoyl) a-1H-1,2,4-triazole-3,5-diamine Given as a light yellow solid.

¹ H NMR (300 MHz, DMSO): δ 7.20 (2H, s), 7.35 (2H, t), 7.45 (2H, d), 7.55 (2H, d), 7.75 ( 1H, m), 8.05 (2H, br s), 9.85 (1H, s)

N ³ -[(4-Aminosulfonyl) phenyl] -1- (2 ′, 6′-difluorobenzoyl) -1H-1,2,4-triazole-3,5-diamine (Compound (Ia))
Stage A:
A mixture of diphenylcyanocarboimidate (DPCCI) (100.0 g, 0.42 mol), 4-aminobenzenesulfonamide (73.0 g, 0.42 mol) and pyridine (350 mL) was added at about 20-30 ° C. at 10 ° C. Stir for hours. The resulting white suspension was then treated with 2,6-difluorobenzoyl hydrazide (84.0 g, 0.49 mol) and then heated to about 70-80 ° C. All starting materials dissolved up to about 40-50 ° C. to give a light brown solution. After 4 hours, the reaction was complete (<2% residual O-phenylisourea) as judged by HPLC analysis.

The light brown solution was then cooled to about 20-25 ° C. and quenched by the addition of 7.5% aqueous NH ₄ Cl (1800 mL). The temperature of the quenching mixture was maintained at about 55-60 ° C. A solid precipitated during quenching. Methanol (100 mL) was then added to the reaction mixture, the reaction mixture was stirred at 55-60 ° C. for 20 minutes, and then the pale yellow suspension was cooled to about 20-25 ° C. The solid was filtered, washed with water (1000 mL) and dried in a vacuum oven at about 90-100 ° C. for 60 hours to give the crude product. This material was used in Step B without further characterization.

KF = 0.86% H ₂ O
Stage B:
The crude solid was stirred in THF (350 mL) at about 55-60 ° C. for 30 minutes and filtered through a celite pad to remove a small amount of insoluble material. The Celite pad was washed with 50-70 mL of THF and the combined clear yellow filtrate and washings were concentrated to a volume of 150 mL at about 60-70 ° C. The product began to crystallize during concentration. Acetonitrile (600 mL) was added to further crystallize the product. The resulting white suspension was cooled to about 0-5 ° C. and the recrystallized product was filtered, washed with acetonitrile (100 mL) and dried overnight. The product was slurried in water (1800 mL) and 50 mL MeOH. The white slurry was heated to 100 ° C. and water (450 mL) was distilled at atmospheric pressure to remove residual acetonitrile. The suspension was then cooled to 20 ° C. and filtered. The solid was washed with water (200 mL), dried in a vacuum oven overnight at about 90 ° C., and N ³ -[(4-aminosulfonyl) phenyl] -1- (2 ′, 6′-difluorobenzoyl) -1H— 1,2,4-Triazole-3,5-diamine was provided as a white solid.

HPLC purity: 98.1 A%, 95.9% by weight
[M + H] ⁺ = 395.0
_{C 15 H 12 F 2 N 6} O 3 S: Analysis Calculated on molecular weight = 394.36: C, 45.68; H , 3.07; F, 9.64; N, 21.31; S, 8 .13
Measurement: C, 45.67; H, 2.87; F, 9.79; N, 21.00; S, 7.76
KF = 0.28% H ₂ O
PXRD, IR and DSC all indicated that this material was crystalline polymorph (Ia-1).

N ³ -[(4-Aminosulfonyl) phenyl] -1- (2 ′, 6′-difluorobenzoyl) -1H-1,2,4-triazole-3,5-diamine (Compound (Ia))
The starting N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester was prepared as described in Example 9, Step A above and was isolated from pyridine.

  N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (1350.0 g, 4.09 mol), 2,6-difluorobenzoyl hydrazide (732.0 g, 4.25 mol) and pyridine (6.75 L) of the mixture was stirred at about 20-30 ° C. until a solution was obtained. The reaction mixture was then heated to about 85-90 ° C. and held at this temperature for 6 hours, after which time the reaction was judged complete by HPLC analysis.

The light brown solution was then cooled to about 20-30 ° C. and quenched into 7.4% aqueous NH ₄ Cl (35.0 L) while maintaining the quenching solution at about 50-60 ° C. Solids were observed to precipitate during quenching. Methanol (1.35 L) was then added to the reaction mixture and the resulting pale yellow suspension was cooled to about 20-25 ° C. The solid was filtered, washed with water (5.4 L) and dried in a vacuum oven overnight at about 85-95 ° C. to give a crude solid.

KF = 1.45% H ₂ O
The crude solid was stirred in THF (5.0 L) at about 20-25 ° C. for 30 minutes and filtered to remove a small amount of insoluble material. The clear yellow filtrate was concentrated to a volume of 3.0 L at about 60-70 ° C., at which point acetonitrile (9.8 L) was added to crystallize the product. The white suspension was cooled to about 0-5 ° C. and filtered. The product was washed with acetonitrile (2.0 L) and then slurried in water (13.5 L). The white suspension was heated to 100 ° C. and water (2.7 L) was distilled to remove residual acetonitrile. The suspension was then cooled to 20 ° C. and filtered to give a white solid.

The white solid was dried overnight and then dissolved in THF (13.7 L). 37% hydrochloric acid (304 mL, 4.29 mol) was then added to the solution of the white solid in THF and the HCl salt of the title compound precipitated almost immediately. The salt was filtered, dried and then re-slurried in water (13.7 L). The resulting white suspension was stirred at ambient temperature until the pH showed no further change (pH meter). At this point the suspension is filtered and the resulting white solid is dried in a vacuum oven at 90 ° C. overnight and N ³ -[(4-aminosulfonyl) phenyl] -1- (2 ′, 6′-difluoro. Benzoyl) -1H-1,2,4-triazole-3,5-diamine was provided as a white solid.

HPLC purity: 99.99% by weight
Melting point 237-239 ° C
MS: [M + H] ⁺ = 395, [M + Na] ⁺ = 417
¹ H NMR (500 MHz, DMSO): δ 7.09 (2H, s), 7.34 (2H, t), 7.47 (2H, d), 7.58 (2H, d), 7.71 ( 1H, m), 8.01 (2H, br s), 9.84 (1H, s)
_{C 15 H 12 F 2 N 6} O 3 Sx0.1H 2 O about Analysis Calculated: C, 45.48; H, 3.10 ; F, 9.59; N, 21.21; S, 8.09 H ₂ O, 0.45
Measurement: C, 45.33; H, 2.99; F, 9.59; N, 21.05; S, 7.76; H ₂ O, 0.38
PXRD, IR and DSC all indicated that this material was crystalline polymorph (Ia-1).

Production title of N ³ -[(4-aminosulfonyl) phenyl] -1- (2 ′, 6′-difluorobenzoyl) -1H-1,2,4-triazole-3,5-diamine (compound (Ia)) A series of experiments was performed to determine the effect of the solvent on the yield determined by HPLC of the compound. The general method for the experiment was as follows. N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (0.5 g, 1.60 mmol) and 2 in 15 ml of the chosen solvent (see Table 3 below) , 6-Difluorobenzoylhydrazide (0.3 g, 1.74 mmol) was stirred and heated to about 80-85 ° C. The reaction mixture was kept at about 80-85 ° C. overnight. After the reaction mixture was cooled to about 20-25 ° C., an aliquot was removed for HPLC analysis. An HPLC sample was prepared by diluting an aliquot with acetonitrile and water (50/50) to determine the% conversion to the title compound and obtained the results as listed in Table 3 below.

Production title of N ³ -[(4-aminosulfonyl) phenyl] -1- (2 ′, 6′-difluorobenzoyl) -1H-1,2,4-triazole-3,5-diamine (compound (Ia)) A series of experiments was performed to determine the effect of solvent and base on the yield determined by HPLC of the compound. The general method for the experiment was as follows. N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (0.5 g, 1.60 mmol) and 2 in 15 ml of the chosen solvent (see Table 4 below) , 6-Difluorobenzoylhydrazide (0.3 g, 1.74 mmol) was added during the addition of (2.08 mmol, 1.3 eq) of the selected base (see Table 4 below). , Stirred. The reaction mixture was heated to about 80-85 ° C. and held at this temperature for 6 hours. After the reaction mixture was cooled to about 20-25 ° C., an aliquot was removed for HPLC analysis. An HPLC sample was prepared by diluting an aliquot with acetonitrile and water (50/50) to determine the% conversion to the title compound and obtained the results as listed in Table 4 below.

CH ₃ SO ₃ H salt of 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide in THF (20 ml) Of 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide (2.0 grams) at room temperature. Stir to form a solution, then CH ₃ SO ₃ H (0.49 g, 0.95 eq) was added. CH ₃ SO ₃ H salt precipitated rapidly. The resulting suspension was stirred at ambient temperature for an additional 20 minutes and the solid was collected by filtration. The filter cake was washed with THF (4 mL) and dried in a vacuum oven at 90 ° C. for 3 days to give the title compound as a white solid, which contained 0.7% CH ₃ CN.

Melting point = 279-281 ° C.
MS: [M + H] ⁺ = 395 (free base)
¹ HNMR (500 MHz, DMSO-d ₆ ): δ 2.43, (3H, s), 7.08 (2H br s), 7.34 (2H, t), 7.46 (2H, d), 7 .58 (2H, d), 7.72 (1H, m), 8.01 (2H, br s), 9.84 (s, 1H)
_{C 16 H 16 F 2 N 6} O 6 S 2, elemental analysis for molecular weight = 490.47:
Calculated: C, 39.18; H, 3.29; F, 7.75; 17.13; S, 13.08
Measurement: C, 39.26; H, 3.12; F, 7.72; N, 17.03; S, 12.98

4- [5-Amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide in HCl salt THF (20 ml) 4- [ A mixture of 5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide (2.0 grams) was stirred and stirred at room temperature. And then 10N HCl (0.48 ml, 0.95 eq) was added. The HCl salt precipitated rapidly. The suspension was stirred at ambient temperature for 20 minutes and the solid was collected by filtration. The filter cake was washed with THF (4 mL) and dried in a vacuum oven at 90 ° C. for 3 days to give the title compound as a white solid, which contained 0.4% CH ₃ CN.

Melting point = 332-334 ° C.
MS: [M + H] ⁺ = 395 (free base)
¹ HNMR (500 MHz, DMSO-d ₆ ): δ 7.10 (2H br s), 7.39 (2H, t), 7.47 (2H, d), 7.57 (2H, d), 7. 72 (1H, m), 8.00 (2H, br s), 9.84 (s, 1H)
Elemental analysis for C ₁₅ H ₁₃ ClF ₂ N ₆ O ₃ S, molecular weight = 430.82:
Calculated values: C, 41.82; H, 3.04; Cl, 8.23; F, 8.82; 19.51; S, 7.44
Measurements: C, 42.04; H, 3.16; Cl, 8.13; F, 8.78; N, 19.50; S, 7.31

4- [5-Amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide HBr salt 4- [ A mixture of 5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide (2.0 grams) was stirred and stirred at room temperature. And then a 48% aqueous solution of HBr (0.56 ml, 0.95 eq) was added. HBr salt precipitated rapidly. The suspension was stirred at ambient temperature for 20 minutes and the solid was collected by filtration. The filter cake was washed with THF (4 mL) and dried in a vacuum oven at 90 ° C. for 3 days to give the title compound as a white solid, which contained 0.9% CH ₃ CN.

Melting point = 258-260 ° C.
MS: [M + H] ⁺ = 395 (free base)
¹ HNMR (500 MHz, DMSO-d ₆ ): δ 7.20 (2H br s), 7.39 (2H, t), 7.47 (2H, d), 7.58 (2H, d), 7. 72 (1H, m), 8.01 (2H, br s), 9.84 (s, 1H)
_{C 15 H 13 BrF 2 N 6} O 3 S, elemental analysis for molecular weight = 475.27:
Calculated: C, 37.91; H, 2.76; Br, 16.81; F, 7.99; 17.68; S, 6.75
Measurement: C, 38.10; H, 2.82; Br, 16.83; F, 7.76; N, 17.63; S, 6.72

4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide 0.5H ₂ SO ₄ salt THF (40 ml) A mixture of 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide (2.0 grams) in room temperature. To give a solution, and then 96% H ₂ SO ₄ (0.48 g, 0.95 eq) was added. H ₂ SO ₄ salt precipitated during 10 minutes. The suspension was stirred for an additional 20 minutes at ambient temperature and the solid was collected by filtration. The filter cake was washed with THF (4 mL) and dried in a vacuum oven at 90 ° C. for 3 days to give the title compound as a white solid, which contained 0.1% CH ₃ CN.

Melting point = 293-295 ° C.
MS: [M + H] ⁺ = 395 (free base)
¹ HNMR (500 MHz, DMSO-d ₆ ): δ 7.09 (2H br s), 7.39 (2H, t), 7.46 (2H, d), 7.57 (2H, d), 7. 72 (1H, m), 8.00 (2H, br s), 9.84 (s, 1H)
_{C 15 H 13 F 2 N 6} O 5 S 1.5, elemental analysis for molecular weight = 443.40:
Calculated: C, 40.63; H, 2.96; F, 8.57; 18.95; S, 10.85
Measurement: C, 40.64; H, 2.90; F, 8.35; N, 18.79; S, 11.01

N- [4- (aminosulfonyl) phenyl] -N′- cyanocarbamic acid phenyl ester of diphenylcyanocarboimidate (DPCCI) (810.31 g, 3.30 mol) in 12.0 L of dimethoxyethane (DME) The white slurry was stirred and heated to 35 ° C. at which point all solids dissolved to give a cloudy solution. The solution was cooled to room temperature to precipitate a small amount of DPCCI. A 480 mL solution of 0.5M ZnCl _{2 in} THF was added, after which the reaction mixture was allowed to stir at room temperature. After stirring overnight, the reaction mixture was cooled to 3 ° C. and 4-aminobenzenesulfonamide (600.0 g, 3.45 mol) was added. The resulting white suspension was stirred and heated to reflux (85 ° C.) while the solid dissolved. After about 1 hour the product began to precipitate. The suspension was stirred at reflux for 7.5 hours and then slowly cooled to 0-5 ° C. The solid was collected by filtration, washed with 2.0 L of DME, dried in a vacuum oven at 28 ″ Hg overnight, and N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester was isolated on white. The material was used in the next step without further characterization.

HPLC purity: 95.7 wt%; 96.3 A%. KF: 0.34% H ₂ O

N ³ -[(4-Aminosulfonyl) phenyl] -1- (2 ′, 6′-difluorobenzoyl) -1H-1,2,4-triazole-3,5-diamine (Compound (Ia))
N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (1206.2 g, 3.60 mol), 2,6-difluorobenzoyl hydrazide (662.95 g, 3.85 mol) and pyridine A mixture of (5.69 L) was stirred at about 20-30 ° C. until a solution was obtained. The reaction mixture was then heated to about 80-90 ° C. and held at this temperature for 6 hours, after which time the reaction was judged complete by HPLC analysis.

The yellow-brown solution is then cooled to about 20-30 ° C. and quenched in 7.5-8.0% aqueous NH ₄ Cl (30.2 L) while maintaining the quenching solution at about 50-60 ° C. Ching. Solids were observed to precipitate during quenching. Methanol (1.00 L) was then added to the reaction mixture and the resulting off-white suspension was stirred at 55-60 ° C. for 30 minutes and then cooled to 15-20 ° C. The solid was filtered, washed with water (4.55 L) and dried in a vacuum oven at 90 ° C. overnight to give the crude product.

KF = 2.5% H ₂ O
A suspension of the crude solid in 4.8 L of THF was heated to 55-60 ° C., stirred for 30 minutes, and then filtered to remove a small amount of insoluble material. The clear filtrate was distilled to remove about 2.8 L of THF, after which 7.0 L of acetonitrile was added and the slurry was heated to 70 ° C. The resulting light brown slurry was cooled to 1.0 ° C. The suspension was filtered. After air drying overnight, the wet solid was suspended in 17.0 L of water, heated to about 100 ° C., and the suspension was distilled to remove about 4.0 L of solution. The slurry is cooled to 10-15 ° C., the product is collected by filtration, washed with 2.0 L of water, dried in a vacuum oven at 90 ° C. and 28 ″ Hg, and N ³ -[(4-aminosulfonyl) Phenyl] -1- (2 ′, 6′-difluorobenzoyl) -1H-triazole-3,5-diamine was provided as a white solid.

HPLC purity: 96.7 wt%; 99.0 A%.
_{C 15 H 12 F 2 N 6} O 3 Sx0.25H 2 O, elemental analysis calculated values for molecular weight = 398.87: C, 45.17; H , 3.16; F, 9.53; N, 21.07 _{; S, 8.04; H 2 O} , 1.13
Measurements: C, 45.00; H, 2.97 ; F, 9.18; N, 20.94; S, 7.96; H 2 O, 1.10
Compound Nos. 8, 13, 19, 24, 26, 27, 32, 33, 34, 36, 37, and 38 are appropriately substituted with appropriately substituted hydrazides under the time and temperature conditions listed in Table 5 below. -Prepared analogously by reacting with a substituted N'-cyanocarbamic acid phenyl ester according to the method of the invention.

N ³ -[(4-aminosulfonyl) phenyl] -1- [3 ′-(trifluoromethyl) benzoyl] -1H-1,2,4-triazole-3,5-diamine (Compound No. 6)
In a clean dry reaction tube, 3- (trifluoromethyl) benzoic acid hydrazide (0.94 g, 4.36 mmol), N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester (1. 34 g, 4.15 mmol) and pyridine (10 mL) were charged sequentially. The suspension was stirred at room temperature for 5-10 minutes to form a solution, after which the reaction mixture was heated to 83 ° C. and stirred at 83-85 ° C. for 4 hours. After 4 hours, the reaction mixture was cooled to room temperature and then added dropwise to a vigorously stirred ice-H ₂ O mixture (ca. 200 mL). A fluffy off-white solid precipitated. Solid sodium chloride (about 20-25 grams) was added to the suspension and it was stirred at 0-5 ° C. for 30 minutes and then filtered. The solid was washed with H ₂ O (about 100 mL) and air dried for 1 hour. The wet solid was dried in a vacuum oven at 80 ° C. for 12 hours under a stream of nitrogen and crude N ³ -[(4-aminosulfonyl) phenyl] -1- [3 ′-(trifluoromethyl) benzoyl] -1H— 1,2,4-Triazole-3,5-diamine was provided as an off-white solid.

The crude product was dissolved in DMSO (4 mL) and purified on a silica gel column (30 g) with a mixture of ethyl acetate / n-heptane (70/30). The product containing fractions were combined and evaporated to give an oily yellow solid containing residual DMSO which was suspended in water (60 mL) and stirred at 50-55 ° C. for 30 min. The suspension was cooled to room temperature and filtered. The solid was then washed with water (30 mL). The product was dried in a vacuum oven at 80 ° C. for 16 hours and N ³ -[(4-aminosulfonyl) phenyl] -1- [3 ′-(trifluoromethyl) benzoyl] -1H-1,2,4- Triazole-3,5-diamine was provided as a pale yellow solid.

HPLC purity: 98.5%
Melting point 251.0-253.0 ° C
MS: [M + H] ⁺ = 427, [M + Na] ⁺ = 449
¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.15 (2H, s), 7.60-7.66 (4H, m), 7.84 (1H, t), 7.95 (2H, br s), 8.07 (1H, d), 8.33 (1H, d), 8.72 (1H, s), 9.87 (1H, s)
_{C 16 H 13 F 3 N 6} O 3 S; molecular weight = 426.38 elemental analysis:
Calculated values: C, 45.07; H, 3.07; N, 19.71; F, 13.37; S, 7.52.
Measurement: C, 44.79; H, 2.94; N, 19.46; F, 12.92; S, 7.66
Although the foregoing specification describes the principles of this invention and examples have been presented for purposes of illustration, the practice of this invention is usually included within the scope of the following claims and their equivalents. It will be understood to encompass all of the variations, applications and / or modifications.

Claims (65)

Formula (I)

[Where:
R ₁ is selected from the group consisting of C _1-8 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
Where cycloalkyl, heterocyclyl, aryl and heteroaryl are:
(A) C _1-8 alkyl (optionally on the terminal carbon —C (O) H, —C (O) (C _1-8 ) alkyl, —CO ₂ (C _1-8 ) alkyl, amino, C ₁ Substituted with a substituent selected from the group consisting of _-8 alkylamino, di (C _1-8 alkyl) amino, cyano, (halo) _1-3 , hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl. be able to),
(B) C _1-8 alkoxy (optionally substituted on the terminal carbon with a substituent selected from the group consisting of (halo) _1-3 and hydroxy),
(C) -C (O) H, -C (O) ( _C1-8 ) alkyl;
_{(D) -CO 2 (C 1-8} ) alkyl;
(E) amino (substituted with two substituents independently selected from the group consisting of hydrogen, C _1-8 alkyl and —SO ₂ — (C _1-8 ) alkyl),
(F) -C (O) amino, wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and _C1-8 alkyl;
(G) —SO ₂ — {heterocyclyl and amino (wherein amino is hydrogen, C _1-8 alkyl, —C _1-8 alkylamino (wherein amino is independently from the group consisting of hydrogen and C _1-8 alkyl) Substituted with 2 substituents selected) and substituted with 2 substituents independently selected from the group consisting of heteroaryl) and substituted with 1 substituent selected from the group consisting of ing},
(H) cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally 1-3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro Can be substituted with;
And where heterocyclyl can be optionally substituted with 1 to 2 oxo substituents; and where cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally C _1-8 alkyl (wherein alkyl is _Is substituted on the terminal carbon with a substituent selected from the group consisting of amino, C _1-8 alkylamino, di (C _1-8 alkyl) amino, cyano, (halo) _1-3 , hydroxy and nitro. And can be substituted with a substituent selected from the group consisting of C _1-8 alkoxy, amino, C _1-8 alkylamino and di (C _1-8 alkyl) amino)
Substituted with a substituent selected from the group consisting of:
R ₃ is: C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl {where C _1-8 alkyl, C _2-8 alkenyl and C _2-8 alkynyl are optionally —C on the terminal carbon (O) H, -C (O ) (C 1-8) _alkyl, -CO _{2 (C 1-8)} alkyl, _{amino, C 1-8} alkylamino, di _{(C 1-8} alkyl) amino, cyano, (Halo) _2-3 , hydroxy, nitro, aryl and heteroaryl, where aryl and heteroaryl are optionally C _1-8 alkyl, cyano, (halo) _1-3 (C _1-8 ) alkyl, (halo) _1-3 Substituted with 1 to 5 substituents independently selected from the group consisting of (C _1-8 ) alkoxy, hydroxy, hydroxy (C _1-8 ) alkyl, hydroxy (C _1-8 ) alkoxy and nitro Can be substituted with a substituent selected from the group consisting of:
Cycloalkyl, heterocyclyl, aryl, heteroaryl {where cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, hydroxy and nitro It is possible;
Where aryl and heteroaryl may be optionally substituted with (halo) _1-3 ;
And where cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally:
(A) C _1-8 alkyl, C _2-8 alkenyl (wherein C _1-8 alkyl and C _2-8 alkenyl are optionally —C (O) H, —C (O) (C _{1 -8) alkyl,} -CO _{2 (C 1-8)} alkyl, _{amino, C 1-8} alkylamino, di _{(C 1-8} alkyl) amino, cyano, _{(halo) 2-3,} hydroxy, nitro, cycloalkyl , Substituted with a substituent selected from the group consisting of heterocyclyl, aryl and heteroaryl),
(B) -CH (OH)-( _C1-8 ) alkyl,
(C) C _1-8 alkoxy (optionally substituted on the terminal carbon with a substituent selected from the group consisting of (halo) _2-3 and hydroxy),
(D) -C (O) H, -C (O) ( _C1-8 ) alkyl;
_{(E) -CO 2 (C 1-8} ) alkyl;
(F) amino (substituted with two substituents independently selected from the group consisting of hydrogen, C _1-8 alkyl and —C (O) (C _1-8 ) alkyl),
(G) -C (O) amino, wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and _C1-8 alkyl;
(H) —SO ₂ — {heterocyclyl and amino (wherein amino is hydrogen, C _1-8 alkyl and —C _1-8 alkylamino (wherein amino is independently from the group consisting of hydrogen and C _1-8 alkyl); Substituted with two substituents independently selected from the group consisting of two substituents selected) and substituted with one substituent selected from the group consisting of} ,
_{(I) -NH-SO 2 -} (C 1-8) alkyl,
(J) substituted with 1 to 2 substituents independently selected from the group consisting of cycloalkyl, heterocyclyl (optionally substituted with 1 to 2 oxo substituents), aryl and heteroaryl Selected from the group consisting of amino;
Where amino is hydrogen, C _1-8 alkyl, cycloalkyl, aryl and heteroaryl (where cycloalkyl, aryl and heteroaryl are optionally C _1-8 alkyl, cyano, (halo) _1-3 (C _{1 -8} ) 1 independently selected from the group consisting of alkyl, (halo) _1-3 (C _1-8 ) alkoxy, hydroxy, hydroxy (C _1-8 ) alkyl, hydroxy (C _1-8 ) alkoxy and nitro Substituted with 2 substituents independently selected from the group consisting of ˜5 substituents);
Provided that when R ³ is aryl or heteroaryl, where aryl or heteroaryl can optionally be substituted with — (CH ₂ ) ₀ -2 —CO ₂ (C _1-8 ) alkyl group, The — (CH ₂ ) _0-2 —CO ₂ (C _1-8 ) alkyl group is not bonded in the ortho position to the bond identified by an asterisk in the compound of formula (I);
Further, provided that when R ³ is cycloalkyl or heterocyclyl, where cycloalkyl or heterocyclyl can be optionally substituted, the substituent on cycloalkyl or heterocyclyl is — (CH ₂ ) _0-2- CO Other than ₂ (C _1-8 ) alkyl]
And a pharmaceutically acceptable salt thereof, comprising:

A suitably substituted compound of formula (II) is reacted with diphenylcyanocarboimidate in a first organic solvent to give the corresponding compound of formula (III);

Reacting a compound of formula (III) with a suitably substituted compound of formula (IV) in a second organic solvent to give the corresponding compound of formula (I).   The method of claim 1, wherein the first organic solvent is pyridine.   The method of claim 2, wherein the second organic solvent is pyridine.   The process according to claim 1, wherein the compound of formula (II) is reacted with diphenylcyanocarboimidate in the presence of a Lewis acid catalyst or a first inorganic or organic base.   The process according to claim 4, wherein the compound of formula (II) is reacted with diphenylcyanocarboimidate in the presence of a first organic base.   6. The method of claim 5, wherein the first organic base is a tertiary amine base.   The method of claim 6 wherein the tertiary amine base is pyridine.   A process according to claim 1, wherein the compound of formula (III) is reacted with a compound of formula (IV) in the presence of a second inorganic or organic base.   9. A process according to claim 8, wherein the compound of formula (III) is reacted with a compound of formula (IV) in the presence of a second organic base.   The method according to claim 9, wherein the second organic base is a tertiary amine base.   The method of claim 10, wherein the tertiary amine base is pyridine.   The process of claim 1, wherein the compound of formula (III) is reacted with the compound of formula (IV) at a temperature in the range of about 80 to about 120 ° C.   13. The method of claim 12, wherein the compound of formula (III) is reacted with the compound of formula (IV) at a temperature in the range of about 80 to about 90 <0> C. The process according to claim 1, wherein R ¹ is 4-aminosulfonylphenyl and R ³ is 2,6-difluorophenyl. Formula (Ia)

A process for producing a compound of

Reacting 4-aminobenzenesulfonamide with diphenylcyanocarboimidate in a first organic solvent to give N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester;

N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid phenyl ester is reacted with 2,6-difluorobenzoic hydrazide in a second organic solvent to give the corresponding compound of formula (Ia) A method comprising providing.   The method of claim 15, wherein the first organic solvent is pyridine.   The process according to claim 16, wherein the second organic solvent is pyridine.   16. A process according to claim 15, wherein the compound of formula (II) is reacted with diphenylcyanocarboimidate in the presence of a Lewis acid catalyst or a first inorganic or organic base.   19. A process according to claim 18, wherein the compound of formula (II) is reacted with diphenylcyanocarboimidate in the presence of a first organic base.   20. The method of claim 19, wherein the first organic base is a tertiary amine base.   21. A process according to claim 20, wherein the tertiary amine base is pyridine.   16. A process according to claim 15, wherein the compound of formula (III) is reacted with a compound of formula (IV) in the presence of a second inorganic or organic base.   23. A process according to claim 22, wherein the compound of formula (III) is reacted with a compound of formula (IV) in the presence of a second organic base.   24. The method of claim 23, wherein the second organic base is a tertiary amine base.   25. The method of claim 24, wherein the tertiary amine base is pyridine.   16. The method of claim 15, wherein the compound of formula (III) is reacted with the compound of formula (IV) at a temperature in the range of about 80 to about 120 <0> C.   27. The method of claim 26, wherein the compound of formula (III) is reacted with the compound of formula (IV) at a temperature in the range of about 80 to about 90 <0> C.   A compound produced according to the method of claim 1.   30. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 28.   30. A pharmaceutical composition prepared by mixing the compound of claim 28 and a pharmaceutically acceptable carrier.   30. A method of preparing a pharmaceutical composition comprising mixing a compound of claim 28 and a pharmaceutically acceptable carrier.   A method of treating or ameliorating a kinase or dual-kinase mediated disorder in a patient in need comprising administering to the patient a therapeutically effective amount of a compound of claim 28.   16. A compound produced according to the method of claim 15.   34. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 33.   34. A pharmaceutical composition prepared by mixing the compound of claim 33 and a pharmaceutically acceptable carrier.   34. A method of preparing a pharmaceutical composition comprising mixing a compound of claim 33 and a pharmaceutically acceptable carrier.   34. A method of treating or ameliorating a kinase or dual-kinase mediated disorder in a patient in need comprising administering to the patient a therapeutically effective amount of a compound of claim 33. The following X-ray diffraction patterns

A crystalline form of 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide comprising   4- [5-Amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzene characterized by a melting endotherm with a peak temperature at about 242 ° C. Crystalline form of sulfonamide.   Reacting 4-aminobenzenesulfonamide with diphenylcyanocarboimidate in the absence of a catalyst; and wherein N- [4- (aminosulfonyl) phenyl] -N′-cyanocarbamic acid ester is converted to 2,6-difluorobenzoic acid 16. The method of claim 15, wherein the N- [4- (aminosulfonyl) phenyl] -N'-cyanocarbamic acid ester is not isolated prior to reacting with the acid hydrazide. (A) A mixture of crystalline forms of 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide in an organic solvent Dissolved in;
(B) reacting the mixture of step (a) with hydrochloric acid to give 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino]- Gives the HCl salt of benzenesulfonamide;
(C) isolating the HCl salt of 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide;
(D) The HCl salt of 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide is suspended in water. 39. The 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazole- according to claim 38, comprising stirring to a constant pH. A method for producing a crystalline form of 3-ylamino] -benzenesulfonamide.   41. A product produced according to the method of claim 40.   43. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 42.   44. A pharmaceutical composition prepared by mixing the compound of claim 43 and a pharmaceutically acceptable carrier.   45. A method of preparing a pharmaceutical composition comprising mixing a compound of claim 42 and a pharmaceutically acceptable carrier.   45. A method of treating or ameliorating a kinase or dual-kinase mediated disorder in a patient in need comprising administering to the patient a therapeutically effective amount of a compound of claim 42. The following X-ray diffraction patterns

A crystalline form of 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide comprising 4-amino-benzenesulfonamide was reacted with diphenyl cyano-carbonitrile imidate in the presence of ZnCl _2; and here N- [4- (aminosulfonyl) phenyl]-N'-cyano carbamates 2,6-difluoro The process according to claim 15, wherein N- [4- (aminosulfonyl) phenyl] -N'-cyanocarbamic acid ester is isolated before reacting with benzoic acid hydrazide.   49. A product produced according to the method of claim 48. CH ₃ SO ₃ H salt of 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide. The molar ratio of 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide to CH ₃ SO ₃ H is 1: 1 is _CH 3 SO ₃ H salt according to claim 50 which is. The following X-ray diffraction patterns

_CH 3 SO ₃ H salt according to claim 50 comprising. Reacting 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide with CH ₃ SO ₃ H. Of CH ₃ SO ₃ H salt of 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide comprising .   HCl salt of 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide.   The molar ratio of 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide to HCl is 1: 1. Item 55. The HCl salt according to Item 54. The following X-ray diffraction patterns

55. The HCl salt according to claim 54, comprising:   4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide comprising reacting with HCl 4- A method for producing the HCl salt of [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide.   HBr salt of 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide.   The molar ratio of 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide to HBr is 1: 1. Item 59. An HBr salt according to Item 58. X-ray diffraction pattern

59. The HBr salt according to claim 58, comprising:   4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide comprising reacting with HBr A method for producing an HBr salt of [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide. H ₂ SO ₄ salt of 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide. The molar ratio of 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide to H ₂ SO ₄ is 1: 0. .5 an _H 2 SO ₄ salt according to claim 62. X-ray diffraction pattern

_H 2 SO ₄ salt according to claim 62 comprising. Reacting 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide with H ₂ SO _4. A process for producing an H ₂ SO ₄ salt of 4- [5-amino-1- (2,6-difluoro-benzoyl) -1H- [1,2,4] triazol-3-ylamino] -benzenesulfonamide.